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3,806 results on '"Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)"'

1. p53 activation during ribosome biogenesis regulates normal erythroid differentiation

Author: François Morlé, Stéphane Giraudier, Eric Soler, Naomi Taylor, Charlotte Andrieu-Soler, Olivier Hermine, Patrick Mayeux, Célia Floquet, Rose Ann Padua, Frédérique Verdier, Sarah Ducamp, Michaela Fontenay, Mohammad Salma, Elisabeth M. Cramer-Borde, Ismael Boussaid, Anna Raimbault, Isabelle Hatin, Diane d'Allard, Amandine Houvert, Narla Mohandas, Boris Guyot, Emilie-Fleur Gautier, Sandrina Kinet, Marjorie Leduc, Pierre-Emmanuel Gleizes, Jean-Jacques Diaz, Salomé Le Goff, François Guillonneau, Nathalie Montel-Lehry, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique, Structure et Traduction (GST), Département Biologie des Génomes (DBG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Hématopoïèse normale et pathologique : émergence, environnement et recherche translationnelle [Paris] ((UMR_S1131 / U1131)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), New York Blood Center, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut de génétique et microbiologie [Orsay] (IGM), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Procédés Alimentaires et Microbiologiques (PAM), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, ANR-18-IDEX-0001,Université de Paris,Université de Paris(2018), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Immunology, Ribosome biogenesis, Biology, Biochemistry, Ribosome, Mice, 03 medical and health sciences, 0302 clinical medicine, Erythroid Cells, Downregulation and upregulation, Transcription (biology), Ribosomal protein, hemic and lymphatic diseases, Animals, Humans, Erythropoiesis, Gene, ComputingMilieux_MISCELLANEOUS, Organelle Biogenesis, RNA, Cell Differentiation, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Hematology, Hematopoietic Stem Cells, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, Organelle biogenesis, Tumor Suppressor Protein p53, Ribosomes
Abstract: The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q− syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis showed that ribosome biogenesis is abruptly interrupted by the decline in ribosomal DNA transcription and the collapse of ribosomal protein neosynthesis. Its premature arrest by the RNA Pol I inhibitor CX-5461 targeted the proliferation of immature erythroblasts. p53 was activated spontaneously or in response to CX-5461, concomitant to ribosome biogenesis arrest, and drove a transcriptional program in which genes involved in cell cycle–arrested, negative regulation of apoptosis, and DNA damage response were upregulated. RNA Pol I transcriptional stress resulted in nucleolar disruption and activation of the ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation is crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold downregulation of ribosome biogenesis could be prematurely reached and, together with pathological p53 activation, prevents a normal expansion of erythroid progenitors.
Published: 2021

2. Regulated expression and function of the GABAB receptor in human pancreatic beta cell line and islets

Author: Rachdi, Latif, Maugein, Alicia, Pechberty, Severine, Armanet, Mathieu, Hamroune, Juliette, Ravassard, Philippe, Marullo, Stefano, Albagli, Olivier, Scharfmann, Raphael, Bodescot, Myriam, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Cell Therapy Unit [Paris], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The work leading to this publication has received support from the Innovative Medicines Initiative 2 Joint Undertaking Rhapsody, under Grant Agreement Nos. 115881 (RHAPSODY) and 115797 (INNODIA) and from Lilly France. The R.S. laboratory is supported by the Dutch Diabetes Research Foundation, by the DON Foundation, by the Fondation pour la Recherche Médicale (EQU201903007793) and by the Fondation Francophone pour la Recherche sur le Diabete (FFRD)., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, lcsh:R, [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], lcsh:Medicine, lcsh:Q, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, lcsh:Science, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. They constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases. We generated a new stable human beta cell line from neonatal pancreas. This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABAB receptor compared to human islet. In ECN90 cells, baclofen, a specific GABAB receptor agonist, inhibits cAMP signaling causing decreased expression of beta cell-specific genes such as MAFA and PCSK1, and reduced insulin secretion. We next demonstrated that in primary human islets, GABBR2 mRNA expression is strongly induced under cAMP signaling, while GABBR1 mRNA is constitutively expressed. We also found that induction and activation of the GABAB receptor in human islets modulates insulin secretion.
Published: 2020

3. Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation

Author: Gaël Nicolas, Thierry Peyrard, Mahmoud Mikdar, Slim Azouzi, Patrick Mayeux, Christine Bole-Feysot, Alexandra Willemetz, Olivier Hermine, Cédric Vrignaud, Marc Cloutier, Emilie-Fleur Gautier, Alexandre Raneri, Virginie Salnot, Maryse St-Louis, Caroline Le Van Kim, Jessica Constanzo-Yanez, Jean-Pierre Cartron, Gabriele Jedlitschky, Nancy Robitaille, Carole Éthier, Patricia Hermand, Patrick Nitschke, Yves Colin, colin, yves, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Institut National de la Transfusion Sanguine [Paris] (INTS), Département Centre National de Référence pour les Groupes Sanguins [Paris], Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Medicine Greifswald, Héma-Québec [Québec], Héma-Québec [Montréal], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), and Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Université des Antilles (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Platelets, 0301 basic medicine, Platelet Aggregation, [SDV]Life Sciences [q-bio], Immunology, ATP-binding cassette transporter, ABCC4, Biology, Biochemistry, 03 medical and health sciences, Cyclic nucleotide, chemistry.chemical_compound, 0302 clinical medicine, Erythroid Cells, Antigen, hemic and lymphatic diseases, medicine, Humans, Gene, integumentary system, Impaired platelet aggregation, Cell Biology, Hematology, medicine.disease, Molecular biology, [SDV] Life Sciences [q-bio], Leukemia, Phenotype, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Blood Group Antigens, biology.protein, CRISPR-Cas Systems, Multidrug Resistance-Associated Proteins, BLOOD Commentary, Gene Deletion, K562 cells
Abstract: The rare PEL-negative phenotype is one of the last blood groups with an unknown genetic basis. By combining whole-exome sequencing and comparative global proteomic investigations, we found a large deletion in the ABCC4/MRP4 gene encoding an ATP-binding cassette (ABC) transporter in PEL-negative individuals. The loss of PEL expression on ABCC4-CRISPR-Cas9 K562 cells and its overexpression in ABCC4-transfected cells provided evidence that ABCC4 is the gene underlying the PEL blood group antigen. Although ABCC4 is an important cyclic nucleotide exporter, red blood cells from ABCC4null/PEL-negative individuals exhibited a normal guanosine 3′,5′-cyclic monophosphate level, suggesting a compensatory mechanism by other erythroid ABC transporters. Interestingly, PEL-negative individuals showed an impaired platelet aggregation, confirming a role for ABCC4 in platelet function. Finally, we showed that loss-of-function mutations in the ABCC4 gene, associated with leukemia outcome, altered the expression of the PEL antigen. In addition to ABCC4 genotyping, PEL phenotyping could open a new way toward drug dose adjustment for leukemia treatment.
Published: 2020

4. Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies

Author: Mélanie Fradin, Nicolas Sadoul, Xavier Waintraub, Didier Klug, Albert Hagège, Pascal Sabouraud, Arnaud Isapof, Julien Durigneux, Olivier Lascols, Pascal Laforêt, Armelle Magot, Ivana Dabaj, Eloi Marijon, Camille Vatier, Pascal Cintas, Emmanuelle Salort, Bénédicte Gaborit, Antoine Muchir, Xavier Ferrer, Pascale Richard, Corinne Metay, Stéphane Boulé, Sarah Leonard-Louis, Philippe Mabo, V. Tiffreau, Caroline Stalens, Jitendra K. Vohra, Stéphane Schaeffer, Khadija Chikhaoui, Eric Bieth, Sandra Mercier, Pierre Ambrosi, Aleksandra Nadaj-Pakleza, Michèle Mayer, Katja Zeppenfeld, Gisèle Bonne, Véronique Manel, Jean-Marc Davy, Guilhem Sole, Ghassan Moubarak, Nicolas Lamblin, Klaus Dieterich, Christophe Meune, Abdallah Fayssoil, Arnaud Lazarus, Philippe Maury, Karim Wahbi, Philippe Petiot, Isabelle Jéru, Annick Toutain, Corinne Vigouroux, Ana Ferreiro, Maud Michaud, H.M. Bécane, Bruno Eymard, Thomas D. Gossios, Marie-Christine Vantyghem, Saurabh Kumar, Estelle Gandjbakhch, Yann Péréon, T. Thompson, Marie-Christine Minot-Myhié, Anthony Behin, Frédéric Sacher, Philippe Charron, Nicolas Combes, Julien Praline, Dominique Babuty, Emmanuelle Lagrue, Usha B. Tedrow, Jean-Marc Sellal, Florence Petit, Perry M. Elliott, Frédéric Anselme, Philippe Chevalier, Frederic Taithe, Christine Barnerias, Vincent Laugel, Andoni Echaniz-Laguna, Raphaël P. Martins, Alexander F.A. Androulakis, Rabah Ben Yaou, Franck Boccara, Ulrike Walther-Louvier, Tanya Stojkovic, Françoise Bouhour, Annachiara De Sandre-Giovannoli, Susana Quijano-Roy, Françoise Chapon, Jean-Noël Trochu, Céline Tard, Anne Rollin, Jean-Marie Cuisset, Denis Duboc, Raphaël Porcher, Catherine Sarret, Jonathan M. Kalman, Florence Demurger, Damien Bonnet, Christine Francannet, Neal K. Lakdawala, Romain Eschalier, Fabien Labombarda, Kostantinos Savvatis, Raul Juntas Morales, Isabelle Desguerre, Nicolas Lévy, Anne-Claire Brehin, Service de Cardiologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU), St Bartholomew's Hospital (London), Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Paris-Centre de Recherche Cardiovasculaire (PARCC (UMR_S 970/ U970)), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Association française contre les myopathies (AFM-Téléthon), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Service de Cardiologie B, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Hôpital Ambroise Paré [AP-HP], William Harvey Research Institute, Barts and the London Medical School, Biostatistique et épidemiologie clinique, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Filière Neuromusculaire (FILNEMUS), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Université de Caen Normandie (UNICAEN), Laboratoire d'Informatique Scientifique et Industrielle (LISI), Université de Poitiers-Ecole Nationale Supérieure de Mécanique et d'Aérotechnique [Poitiers] (ISAE-ENSMA), Hôpital Raymond Poincaré [AP-HP], CHU Lille, Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Aix Marseille Université (AMU), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de cardiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de cardiologie et maladies vasculaires [Rennes] = Cardiac, Thoracic, and Vascular Surgery [Rennes], CHU Pontchaillou [Rennes], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinique Pasteur [Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Imagerie Adaptative Diagnostique et Interventionnelle (IADI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), The Royal Melbourne Hospital, Leiden University Medical Center (LUMC), Universiteit Leiden, Service de neurologie pédiatrique [CHU Necker], Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), CHU Necker - Enfants Malades [AP-HP], Hôpital Privé Le Bois Ramsay Santé [Lille], Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Mobilités : Vieillissement, Pathologie, Santé (COMETE), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Roger Salengro [Lille], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre de ressources biologiques Tissus ADN Cellules [Hôpital de la Timone - APHM] (CRB TAC), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Cytogénétique et de Biologie Cellulaire, Université de Rennes (UR)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Centre Hospitalier Universitaire [Grenoble] (CHU), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Les Hôpitaux Universitaires de Strasbourg (HUS), CHU Clermont-Ferrand, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie [Bordeaux], Service de Génétique Médicale [CHU Clermont-Ferrand], CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie cadiovasculaire et thoracique [Rouen], Hôpital Charles Nicolle [Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Service de cardiologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Trousseau [APHP], Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Strasbourg, Clinique Ambroise Paré [Centres Médico-Chirurgicaux Ambroise Pré, Pierre Cherest, Hartmann], Hôpital Cochin [AP-HP], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Lorraine (UL), Service de neurologie [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Centre hospitalier universitaire de Nantes (CHU Nantes), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre Hospitalier Universitaire de Reims (CHU Reims), Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de Neurologie [CHU Clermont-Ferrand], CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Laboratoire d'étude de la motricité humaine - EA 3608 (LEMH), Université de Lille, Droit et Santé, Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Physiopathologie et thérapie du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montréal (UdeM), Laboratoire Génie des procédés papetiers (LGP2 ), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), The Heart Hospital [London], University College of London [London] (UCL), This study was funded by grants from the AFM-Téléthon (French Alliance against Myopathies), which was not involved in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, or approval of the manuscript, and decision to submit the manuscript for publication. Some of this work was undertaken at University College London (United Kingdom) and St. Bartholomew’s Hospital (London, United Kingdom), which received a portion of funding from the United Kingdom Department of Health’s National Institute for Health Research Biomedical Research Centres funding scheme., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], CHU Bordeaux [Bordeaux]-Université Bordeaux Segalen - Bordeaux 2, Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-CHU Trousseau [APHP], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de cardiologie et maladies vasculaires, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Unit of Neuromuscular Morphology [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP]-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des maladies rares neuromusculaires Aquitaine-Grand Sud Ouest, CHU Bordeaux [Bordeaux], Laboratoire d'Informatique Scientifique et Industrielle (LISI / ENSMA), LISI-ENSMA, Service de Biochimie-Génétique [Béclère], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Thérapie des maladies du muscle strié, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Cardiologie A, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d'Endocrinologie et Métabolisme, Unité de Cardiologie et Soins Intensifs, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Service de Génétique [Purpan], CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Centre de Référence M3C Malformations Cardiaques Congénitales Complexes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Hôpital neurologique, Centre Hospitalier Universitaire de Lille (CHU de Lille), Service Neurologie Pédiatrique, Service de Neuropédiatrie, INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Département de Neurologie, Hôpital Civil de Strasbourg, Groupe Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU - HÔTEL-DIEU Clermont-Ferrand, CLAD Ouest, Centre Hospitalier Universitaire [Rennes], Centre recherche en CardioVasculaire et Nutrition (C2VN), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagerie et cerveau, Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Clinique Ambroise Paré, CHU Cochin [AP-HP], Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hopital Neurologique-Hôpital Femme Mère Enfant, Department of Medicine, Columbia University [New York]-College of Physicians and Surgeons, Service de neurologie, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Hôpital de Rangueil, Institut Pascal - Clermont Auvergne (IP), Sigma CLERMONT (Sigma CLERMONT)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'étude de la motricité humaine (LEMH EA3608), Université de Montréal - UdeM (CANADA), Laboratoire Génie des procédés papetiers (LGP2), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Myologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Sorbonne Université, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut de Myologie, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), European Genomic Institute for Diabetes - FR 3508 (EGID), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Hôpital Purpan [Toulouse], Hôpital Charles Nicolle [Rouen]-CHU Rouen, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut de Myologie, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, Tachycardia, medicine.medical_specialty, implantable, Accurate estimation, Ventricular Tachyarrhythmias, Validation Studies as Topic, 030204 cardiovascular system & hematology, tachycardia, Sudden death, LMNA, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, death, Physiology (medical), Internal medicine, defibrillators, medicine, Humans, In patient, 030212 general & internal medicine, sudden, [SDV.GEN]Life Sciences [q-bio]/Genetics, Prediction score, business.industry, Defibrillators, Implantable, ventricular, Tachycardia, Ventricular, Cardiology, Female, medicine.symptom, Cardiomyopathies, Cardiology and Cardiovascular Medicine, business
Abstract: Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.
Published: 2019

5. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study

Author: Brüggemann, Monika, Kotrova, Michaela, Knecht, Henrik, Bartram, Jack, Boudjogrha, Myriam, Bystry, Vojtech, Fazio, Grazia, Froňková, Eva, Giraud, Mathieu, Grioni, Andrea, Hancock, Jeremy, Herrmann, Dietrich, Jimenez, Cristina, Krejci, Adam, Moppett, John, Reigl, Tomas, Salson, Mikaël, Scheijen, Blanca, Schwarz, Martin, Songia, Simona, Svaton, Michael, van Dongen, Jacques, Villarese, Patrick, Wakeman, Stephanie, Wright, Gary, Cazzaniga, Giovanni, Davi, Frédéric, García-Sanz, Ramón, Davi, David, Groenen, Patricia, Hummel, Michael, Macintyre, Elizabeth, Stamatopoulos, Kostas, Pott, Christiane, Trka, Jan, Darzentas, Nikos, Langerak, Anton, Gonzalez, David, Bruggemann, M, Kotrova, M, Knecht, H, Bartram, J, Boudjogrha, M, Bystry, V, Fazio, G, Fronkova, E, Giraud, M, Grioni, A, Hancock, J, Herrmann, D, Jimenez, C, Krejci, A, Moppett, J, Reigl, T, Salson, M, Scheijen, B, Schwarz, M, Songia, S, Svaton, M, van Dongen, J, Villarese, P, Wakeman, S, Wright, G, Cazzaniga, G, Davi, F, Garcia-Sanz, R, Gonzalez, D, Groenen, P, Hummel, M, Macintyre, E, Stamatopoulos, K, Pott, C, Trka, J, Darzentas, N, Langerak, A, Immunology, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Childhood Leukaemia Investigation Prague (CLIP), University Hospital Motol [Prague], Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 (CRIStAL), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille, Facultad de Quimica, Universidad Nacional Autonoma de Mexico, Bioinformatics and Sequence Analysis (BONSAI), Laboratoire d'Informatique Fondamentale de Lille (LIFL), Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Sciences et Technologies-Institut National de Recherche en Informatique et en Automatique (Inria)-Université de Lille, Sciences Humaines et Sociales-Centre National de la Recherche Scientifique (CNRS)-Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria), Liebherr-Werk Nenzing GmbH, Department of Immunology, Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bristol Genetics Laboratory, Southmead Hospital, North Bristol NHS Trust, Great Ormond Street Hospital for Children [London] (GOSH), Service d'Hématologie Clinique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Haematology Department, University Hospital of Salamanca, Hematology Department and University Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France, Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands., Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, CHU Necker - Enfants Malades [AP-HP], Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Sweden, University Hospital Schleswig–Holstein, Department of Paediatric Haematology/Oncology, Charles University [Prague], Central European Institute of Technology, Masaryk University, Brno, Czech Republic, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Paediatric Haematology, Department of Hematology, University Hospital Schleswig-Holstein [Kiel, Germany], Service d'Hématologie clinique [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Central European Institute of Technology [Brno] (CEITEC MU), Brno University of Technology [Brno] (BUT), Centro Ricerca Tettamanti, Clinica Pediatrica, Ospedale S. Gerardo-Ospedale S. Gerardo, Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Bristol Genetics Laboratory (Southmead Hospital), Southmead Hospital, Instituto de Investigación Biomédica de Salamanca (IBSAL), Department of Pediatric Haematology, Bristol Royal Hospital for Children, Department of Pathology [Nijmegen], Radboud University Medical Center [Nijmegen], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité d'Immunologie et d'Hématologie Pédiatrique (CHU Necker - Enfants Malades [AP-HP]), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Institute of Applied Biosciences, Thessaloniki, Greece., Charles University [Prague] (CU), Centre for Cancer Research and Cell Biology, Queen's University [Belfast] (QUB), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Genetic Markers, 0301 basic medicine, Cancer Research, Neoplasm, Residual, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Receptors, Antigen, T-Cell, Immunoglobulins, Computational biology, Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9], Gene Rearrangement, T-Lymphocyte, Article, DNA sequencing, 03 medical and health sciences, symbols.namesake, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Genetics research, Multiplex polymerase chain reaction, Humans, Cancer genetics, Recombination, Genetic, Sanger sequencing, minimal residual disease, next generation sequencing immunoglobulin and T-cell receptor, Genes, Immunoglobulin, biology, Computational Biology, High-Throughput Nucleotide Sequencing, Reproducibility of Results, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Gene rearrangement, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Reference Standards, Amplicon, Minimal residual disease, 3. Good health, Genes, T-Cell Receptor, 030104 developmental biology, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Oncology, 030220 oncology & carcinogenesis, symbols, biology.protein, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Antibody, Primer (molecular biology)
Abstract: International audience; Amplicon-based next-generation sequencing (NGS) of immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements for clonality assessment, marker identification and quantification of minimal residual disease (MRD) in lymphoid neoplasms has been the focus of intense research, development and application. However, standardization and validation in a scientifically controlled multicentre setting is still lacking. Therefore, IG/TR assay development and design, including bioinformatics, was performed within the EuroClonality-NGS working group and validated for MRD marker identification in acute lymphoblastic leukaemia (ALL). Five EuroMRD ALL reference laboratories performed IG/TR NGS in 50 diagnostic ALL samples, and compared results with those generated through routine IG/TR Sanger sequencing. A central polytarget quality control (cPT-QC) was used to monitor primer performance, and a central in-tube quality control (cIT-QC) was spiked into each sample as a library-specific quality control and calibrator. NGS identified 259 (average 5.2/sample, range 0–14) clonal sequences vs. Sanger-sequencing 248 (average 5.0/sample, range 0–14). NGS primers covered possible IG/TR rearrangement types more completely compared with local multiplex PCR sets and enabled sequencing of bi-allelic rearrangements and weak PCR products. The cPT-QC showed high reproducibility across all laboratories. These validated and reproducible quality-controlled EuroClonality-NGS assays can be used for standardized NGS-based identification of IG/TR markers in lymphoid malignancies.
Published: 2019

6. Successful in utero stem cell transplantation in X-linked severe combined immunodeficiency

Author: Aurélie Gabrion, Elisabeth A. Macintyre, Emmanuel Clave, Anne-Marie Darras, Alessandra Magnani, Stéphane Blanche, Brigitte Ternaux, Antoine Toubert, Capucine Picard, Marina Cavazzana, Cécile Roudaut, Laure Caccavelli, Jérémie Rosain, Elisa Magrin, Nizar Mahlaoui, Jennifer Nisoy, Fabien Touzot, Marion Alcantara, Isabelle Radford-Weiss, Jean-Marie Jouannic, Sven Kracker, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Centre pluridisciplinaire de diagnostic prénatal [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], CHU Necker - Enfants Malades [AP-HP], Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie et d'Histocompatibilité, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'étude des proliférations lymphoïdes (GPL), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Humaine des Maladies Infectieuses (Inserm U980), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: Transplantation Conditioning, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hematopoietic stem cell transplantation, X-Linked Combined Immunodeficiency Diseases, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Humans, X-linked severe combined immunodeficiency, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Severe combined immunodeficiency, business.industry, Hematopoietic Stem Cell Transplantation, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, medicine.disease, Stimulus Report, 3. Good health, Transplantation, medicine.anatomical_structure, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, In utero, Child, Preschool, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Bone marrow, Stem cell, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Key Points IUT enables rapid immune reconstitution and avoids many clinical and economic problems; however, the indication is still limited. IUT may be a treatment option in select cases, eg, fetuses exposed to a significant infectious risk, where a matched sibling donor exists.
Published: 2019

7. Molecular epidemiology of invasive and non-invasive group B Streptococcus circulating in Serbia

Author: Lazar Ranin, Philippe Glaser, Claire Poyart, Ina Gajic, Céline Plainvert, Asmaa Tazi, Dusan Kekic, Nicolas Dmytruk, Vera Mijac, Natasa Opavski, Institute of Microbiology and Immunology [Belgrade, Serbia] (School of Medicine), University of Belgrade [Belgrade], National Reference Laboratory for Streptococci, Medical Faculty, University of Belgrade, Service de Bactériologie [CHU Cochin, AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre national de Référence des Streptocoques (CNR), DHU Risques Et Grossesse, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Barrières et Pathogènes, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This study was supported by the Federation of European Microbiological Societies [FEMS-RG-2014-0025.R1] and the SerbianMinistry of Education and Science [Project No175039]., BOUYSSIE, Reine, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)
Subjects: MESH: Adhesins, Bacterial, medicine.disease_cause, Group B, MESH: Pregnancy, MESH: Streptococcal Infections, Pregnancy, Drug Resistance, Multiple, Bacterial, Prevalence, Clustered Regularly Interspaced Short Palindromic Repeats, Colonization, Capsular type, 0303 health sciences, MESH: Clindamycin, Streptococcus, Clindamycin, General Medicine, MESH: Infant, 3. Good health, Infectious Diseases, CRISPR, Female, Serbia, Adult, Microbiology (medical), clone (Java method), Penicillins, Biology, Microbiology, Streptococcus agalactiae, 03 medical and health sciences, MESH: Penicillins, Streptococcal Infections, MESH: Bacterial Capsules, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, medicine, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Adhesins, Bacterial, MESH: Prevalence, Bacterial Capsules, Hyper-virulent clone ST17, 030304 developmental biology, MESH: Humans, Molecular epidemiology, 030306 microbiology, Pregnant women, Neonates, Infant, MESH: Adult, MESH: Drug Resistance, Multiple, Bacterial, MESH: Streptococcus agalactiae, MESH: Serbia, Colonisation, MESH: Clustered Regularly Interspaced Short Palindromic Repeats, Multilocus sequence typing, MESH: Female
Abstract: International audience; Streptococcus agalactiae (group B Streptococcus, GBS) remains the leading cause of invasive diseases in neonates and an important cause of infections in the elderly. The aim of this study was to access the prevalence of GBS genito-rectal colonisation of pregnant women and to evaluate the genetic characteristics of invasive and non-invasive GBS isolates recovered throughout Serbia. A total of 432 GBS isolates were tested for antimicrobial susceptibility, capsular polysaccharide (CPS) types and the presence of the hvgA gene. One hundred one randomly selected isolates were further characterized by clustered regularly interspaced short palindromic repeats (CRISPRs) analysis and/or multilocus sequence typing (MLST). The prevalence of GBS colonization in pregnant women was 15%. Overall, six capsular types (Ia, Ib, II to V) were identified, the most common being III (32.2%) and V (25.2%). The hiper-virulent clone type III/ST17 was present in 43.1% and 6.3% (p
Published: 2019

8. The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research

Author: Jie Li, Ben Shen, Orazio Taglialatela-Scafati, Matthias Niemitz, Sonja Sturm, Jian Min Yue, Andrei G. Kutateladze, Craig M. Williams, Nicholas H. Oberlies, Phillip Crews, Jean-Hugues Renault, Hermann Stuppner, John B. MacMillan, David Coppage, Harald Gross, Bin Gui Wang, Hiroyuki Koshino, Shao-Nong Chen, Bradley S. Moore, Carla M. Saunders, Jonathan Bisson, Andersson Barison, Miaomiao Liu, David G. I. Kingston, Young Hae Choi, Dean J. Tantillo, Mary J. Garson, Christoph Seger, Mehdi A. Beniddir, Hsiau Wei Lee, Wolfgang Robien, Zhengren Xu, Maique W. Biavatti, Tadeusz F. Molinski, David C. Lankin, Stefan Bluml, Damien Jeannerat, Philip G. Williams, José Rivera-Chávez, Julien Wist, Grégory Genta-Jouve, Ram P. Neupane, James B. McAlpine, Chen Zhang, Ronald J. Quinn, Joo-Won Nam, William H. Gerwick, Giovanni Appendino, Fernanda Maria Marins Ocampos, Jean-Marc Nuzillard, Joseph M. Egan, Luke Hunter, Marie Csete, Guohui Pan, Robert Verpoorte, Roger G. Linington, Tyler A. Johnson, Precilia Hermanto, Kerry L. McPhail, Mark S. Butler, Guy Lewin, Charlotte Simmler, Guido F. Pauli, Michael T. Crimmins, Mary Kay Harper, Thomas J. Schmidt, Christoph Steinbeck, James M. Hook, Nai Yun Ji, D. Sai Reddy, Asmaa Boufridi, Robert J. Capon, Pradeep Dewapriya, Jeannerat, Damien, Mcalpine, James B, Chen, Shao-Nong, Kutateladze, Andrei, Macmillan, John B, Appendino, Giovanni, Barison, Andersson, Beniddir, Mehdi A, Biavatti, Maique W, Bluml, Stefan, Boufridi, Asmaa, Butler, Mark S, Capon, Robert J, Choi, Young H, Coppage, David, Crews, Phillip, Crimmins, Michael T, Csete, Marie, Dewapriya, Pradeep, Egan, Joseph M, Garson, Mary J, Genta-Jouve, Grégory, Gerwick, William H, Gross, Harald, Harper, Mary Kay, Hermanto, Precilia, Hook, James M, Hunter, Luke, Nai-Yun, Ji, Johnson, Tyler A, Kingston, David G I, Koshino, Hiroyuki, Lee, Hsiau-Wei, Lewin, Guy, Jie, Li, Linington, Roger G, Liu, Miaomiao, Mcphail, Kerry L, Molinski, Tadeusz F, Moore, Bradley S, Nam, Joo-Won, Neupane, Ram P, Niemitz, Matthia, Nuzillard, Jean-Marc, Oberlies, Nicholas H, Ocampos, Fernanda M M, Pan, Guohui, Quinn, Ronald J, Reddy, D Sai, Renault, Jean-Hugue, Rivera-Chávez, José, Robien, Wolfgang, Saunders, Carla M, Schmidt, Thomas J, Seger, Christoph, Shen, Ben, Steinbeck, Christoph, Stuppner, Hermann, Sturm, Sonja, Taglialatela-Scafati, Orazio, Tantillo, Dean J, Verpoorte, Robert, Wang, Bin-Gui, Williams, Craig M, Williams, Philip G, Wist, Julien, Yue, Jian-Min, Zhang, Chen, Zhengren, Xu, Simmler, Charlotte, Lankin, David C, Bisson, Jonathan, Pauli, Guido F, Thallion Pharmaceuticals Inc., Brunel University London [Uxbridge], Dipartimento di Scienze Chimiche, DIPARTIMENTO DI SCIENZE CHIMICHE, Departamento de Química, Universidade Federal do Paraná (UFPR), Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Equipe C-TAC (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Sorbonne Paris Cité (USPC), University of Tübingen, University of New South Wales [Sydney] (UNSW), Department of organic Chemistry - University of Geneva, University of Geneva [Switzerland], Department of Chemistry and Biochemistry, University of California, University of California [Santa Cruz] (UCSC), University of California-University of California, Center for Marine Biotechnology and Biomedicine, University of California, Institut de Chimie Moléculaire de Reims - UMR 7312 (ICMR), SFR Condorcet, Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS)-SFR CAP Santé (Champagne-Ardenne Picardie Santé), Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chinese Academy of Sciences [Beijing] (CAS), University of Münster, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of Innsbruck, Section Metabolomics (DIVISION OF PHARMACOGNOSY), Universiteit Leiden [Leiden]-Institute of Biology, Institut National de l'Environnement Industriel et des Risques (INERIS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), and Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Université de Picardie Jules Verne (UPJV)-Université de Reims Champagne-Ardenne (URCA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: NMR, Natural Products, Raw Data, Reproducibility, Value (ethics), Magnetic Resonance Spectroscopy, Molecular Conformation, [CHIM.INOR]Chemical Sciences/Inorganic chemistry, 010402 general chemistry, Medical and Health Sciences, 01 natural sciences, Biochemistry, Article, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Component (UML), Drug Discovery, Dissemination, Biological Products, Biological studies, 010405 organic chemistry, Organic Chemistry, Reproducibility of Results, Biological Sciences, Transparency (behavior), Data science, Nmr data, 0104 chemical sciences, Chemical Sciences, ddc:540, Generic health relevance, Natural Product Research, Raw data, [CHIM.CHEM]Chemical Sciences/Cheminformatics
Abstract: International audience; With contributions from the global natural product (NP) research community, and continuing the Raw Data Initiative, this review collects a comprehensive demonstration of the immense scientific value of disseminating raw nuclear magnetic resonance (NMR) data, independently of, and in parallel with, classical publishing outlets. A comprehensive compilation of historic to present-day cases as well as contemporary and future applications show that addressing the urgent need for a repository of publicly accessible raw NMR data has the potential to transform natural products (NPs) and associated fields of chemical and biomedical research. The call for advancing open sharing mechanisms for raw data is intended to enhance the transparency of experimental protocols, augment the reproducibility of reported outcomes, including biological studies, become a regular component of responsible research, and thereby enrich the integrity of NP research and related fields.
Published: 2019

9. Calibrated photoacoustic spectrometer for in vitro characterization of contrast agents based on a standard imaging system

Author: Sarkar, Mitradeep, Lucas, Théotim, Atlas, Yoann, Renault, Gilles, Gazeau, Florence, Gateau, Jérôme, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Plateforme Imagerie du petit animal [Institut Cochin], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPC)
Subjects: [PHYS.PHYS.PHYS-OPTICS]Physics [physics]/Physics [physics]/Optics [physics.optics]
Abstract: Photoacoustic (PA) contrast agents are usually characterized with spectrophotometry or uncalibrated PA imaging systems, leading to partial assessment of their PA efficiency. To perform calibrated PA spectroscopy with a PA imaging system, we developed a method that simultaneously corrects for the spectral energy distribution of excitation light and performs a conversion from arbitrary to spectroscopic units, using a calibration solution of cupric sulfate. The method was implemented on a standard imaging set-up based on a tunable laser operating between 680nm and 980nm and a 5MHz clinical ultrasound array. We demonstrated robust calibrated PA spectroscopy with 15μL sample volumes of known chromophores and commonly used contrast agents, and for up to 4 samples simultaneously. The detection sensitivity was evaluated to be below 0.05 cm -1 in the range 680-930 nm.
Published: 2021

10. Beta-arrestins operate an on/off control switch for focal adhesion kinase activity

Author: Stefano Marullo, Aurélie Borrull, Mireille Lambert, Isaure Lot, Alexandre Beautrait, Michel Bouvier, Revu Ann Alexander, Kusumika Saha, Eleonore Decosta, Mark G.H. Scott, Atef Asnacios, Hervé Enslen, Guillaume Abadie, Hiroyuki Kobayashi, [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Biochemistry [Montreal, QC, Canada] (Institute for Research in Immunology and Cancer), Université de Montréal (UdeM), Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Enslen, Hervé, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Scaffold protein, genetic structures, [SDV]Life Sciences [q-bio], G-protein-coupled receptors, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Receptors, G-Protein-Coupled, Mice, 0302 clinical medicine, Neoplasms, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Phosphorylation, beta-Arrestins, ComputingMilieux_MISCELLANEOUS, 0303 health sciences, FERM domain, Chemistry, Autophosphorylation, Cell biology, [SDV] Life Sciences [q-bio], 030220 oncology & carcinogenesis, Molecular Medicine, Arrestin beta 2, biological phenomena, cell phenomena, and immunity, G proteins, Protein Binding, G protein, Vasopressins, Adaptor Protein Complex 2, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Receptor, Angiotensin, Type 1, Focal adhesion, 03 medical and health sciences, Cellular and Molecular Neuroscience, [SDV.CAN] Life Sciences [q-bio]/Cancer, Protein Domains, GTP-Binding Proteins, Animals, Humans, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Molecular Biology, 030304 developmental biology, G protein-coupled receptor, Pharmacology, Beta-arrestin, FAK, Beta-Arrestins, Cell Membrane, β-Arrestin, Cell Biology, AP-2, HEK293 Cells, Focal Adhesion Protein-Tyrosine Kinases, Multiprotein Complexes, sense organs
Abstract: International audience; Focal adhesion kinase (FAK) regulates key biological processes downstream of G protein-coupled receptors (GPCRs) in normal and cancer cells, but the modes of kinase activation by these receptors remain unclear. We report that after GPCR stimulation, FAK activation is controlled by a sequence of events depending on the scaffolding proteins β-arrestins and G proteins. Depletion of β-arrestins results in a marked increase in FAK autophosphorylation and focal adhesion number. We demonstrate that β-arrestins interact directly with FAK and inhibit its autophosphorylation in resting cells. Both FAK-β-arrestin interaction and FAK inhibition require the FERM domain of FAK. Following the stimulation of the angiotensin receptor AT1AR and subsequent translocation of the FAK-β-arrestin complex to the plasma membrane, β-arrestin interaction with the adaptor AP-2 releases inactive FAK from the inhibitory complex, allowing its activation by receptor-stimulated G proteins and activation of downstream FAK effectors. Release and activation of FAK in response to angiotensin are prevented by an AP-2-binding deficient β-arrestin and by a specific inhibitor of β-arrestin/AP-2 interaction; this inhibitor also prevents FAK activation in response to vasopressin. This previously unrecognized mechanism of FAK regulation involving a dual role of β-arrestins, which inhibit FAK in resting cells while driving its activation at the plasma membrane by GPCR-stimulated G proteins, opens new potential therapeutic perspectives in cancers with up-regulated FAK.
Published: 2020

11. A sensitive S-Trap-based approach to the analysis of T cell lipid raft proteome

Author: Chhuon, Cerina, Zhang, Shao-Yu, Jung, Vincent, Lewandowski, Daniel, Lipecka, Joanna, Pawlak, Andre, Sahali, Dil, Ollero, Mario, Guerrera, Ida Chiara, Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Est Créteil, IMRB - PGD/'Pathophysiology of Glomerular Diseases' [Créteil] (U955 Inserm - UPEC), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Laboratoire de Recherche sur la Réparation et la Transcription dans les Cellules Souches (LRTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Stabilité génétique, cellules souches et radiations (SGCSR (U_1274 / UMR_E_008)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université Paris Cité (UPCité), Université Paris Diderot, Sorbonne Paris Cité, Paris, France, Université Paris Diderot - Paris 7 (UPD7), Université Paris Sud (Université Paris Sud), AP-HP, Groupe Henri-Mondor Albert-Chenevier, Service de Néphrologie, Université Paris-Est Créteil, Créteil, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), IMRB - 'Transfusion et Maladies du Globule Rouge' [Créteil] (U955 Inserm - UPEC), Université Paris Diderot - Paris 7 (UPD7)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Paris (UP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Inserm U955, équipe 21, Service de néphrologie et transplantation, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Canalopathies épithéliales: la mucoviscidose et autres maladies, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Ollero, Mario
Subjects: lymphocytes, S-trap : Filter aided sample preparation, Proteome, detergent-free, T-Lymphocytes, [SDV]Life Sciences [q-bio], QD415-436, OptiPrep, Biochemistry, raftomics, immunology, Mice, FASP, tandem mass spectrometry, Methods, Animals, Humans, tandem mass-spectrometry, cell signaling, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Mice, Inbred BALB C, LAT: linker for activation of T cells, TCR: T cell receptor immunology, detergentfree, Lipids, [SDV] Life Sciences [q-bio], HEK293 Cells, membranes, FASP : Filter aided sample preparation, lipids (amino acids, peptides, and proteins), Chromatography, Liquid
Abstract: International audience; The analysis of T cell lipid raft proteome is challenging due to the highly dynamic nature of rafts and the hydrophobic character of raft-resident proteins. We explored an innovative strategy for bottom-up lipid raftomics based on suspension trapping (S-trap) sample preparation. Mouse T cells were prepared from splenocytes by negative immunoselection and rafts were isolated by a detergent-free method and OptiPrep gradient ultracentrifugation. Microdomains enriched in Flotillin-1, LAT and cholesterol were subjected to proteomic analysis through an optimized protocol based on STrap and high pH fractionation, followed by nano-LC-MS/MS. Using this method, we identified 2680 proteins in the raft-rich fraction and established a database of 894 T cell raft proteins. We then performed a differential analysis on the raft-rich fraction from non-stimulated vs. anti-CD3/CD28 TCR-stimulated T cells. Our results revealed 42 proteins present in one condition and absent in the other. For the first time, we performed a proteomic analysis on rafts from ex-vivo T cells obtained from individual mice, before and after TCR activation. This work demonstrates that the proposed method utilizing an Strap based approach for sample preparation increases the specificity and sensitivity of lipid raftomics. Data are available via ProteomeXchange with identifier PXD016476.
Published: 2020

12. Photothermal Depletion of Cancer-Associated Fibroblasts Normalizes Tumor Stiffness in Desmoplastic Cholangiocarcinoma

Author: Gilles Renault, Gautier Laurent, Emmanuel Donnadieu, Laura Fouassier, Florence Gazeau, Alba Nicolas-Boluda, Rana Bazzi, Javier Vaquero, Stéphane Roux, Université de Paris, Institut Cochin, Institut National de la Santé et de la Recherche Médicale INSERM U1016, Centre National de la Recherche Scientifique CNRS UMR8104, F-75014 Paris isabelle.dusanter@inserm.fr., Matière et Systèmes Complexes (MSC (UMR_7057)), Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Univers, Transport, Interfaces, Nanostructures, Atmosphère et environnement, Molécules (UMR 6213) (UTINAM), Institut national des sciences de l'Univers (INSU - CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Plateforme Imagerie du petit animal [Institut Cochin], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Debray, Bernard, Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV]Life Sciences [q-bio], Population, General Physics and Astronomy, Metal Nanoparticles, [SDV.CAN]Life Sciences [q-bio]/Cancer, 02 engineering and technology, medicine.disease_cause, Extracellular matrix, Cholangiocarcinoma, 03 medical and health sciences, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, Stroma, Cancer-Associated Fibroblasts, [CHIM] Chemical Sciences, medicine, Tumor Microenvironment, Humans, [CHIM]Chemical Sciences, General Materials Science, education, ComputingMilieux_MISCELLANEOUS, education.field_of_study, Tumor microenvironment, Chemistry, General Engineering, Cancer, Photothermal therapy, Fibroblasts, 021001 nanoscience & nanotechnology, medicine.disease, 3. Good health, Bile Ducts, Intrahepatic, Bile Duct Neoplasms, 030220 oncology & carcinogenesis, Cancer research, Gold, 0210 nano-technology, Carcinogenesis
Abstract: Physical oncology recognizes tissue stiffness mediated by activation of cancer-associated fibroblasts (CAF) and extracellular matrix remodeling as an active modulator of tumorigenesis, treatment resistance, and clinical outcome. Cholangiocarcinoma (CCA) is a highly aggressive and chemoresistant desmoplastic cancer enriched in CAF. CCA's stroma mechanical properties are considered responsible for its chemoresistant character. To normalize tumor mechanics, we propose a physical strategy based on remotely light-activated nanohyperthermia to modulate the tumor microenvironment. In this study, we report the use of multifunctional iron oxide nanoflowers decorated with gold nanoparticles (GIONF) as efficient nanoheaters to achieve complete tumor regression following three sessions of mild hyperthermia. The preferential uptake of GIONF by CAF allowed targeting this cell population, which resulted in a significant early reduction of tumor stiffness followed by tumor regression. In conclusion, our study highlights a spatially and temporally controlled physical strategy, GIONF-mediated photothermal therapy to deplete CAF and normalize the tumor mechanics that may apply to desmoplastic cancer and CCA treatment.
Published: 2020

13. Mechanical GPCR Activation by Traction Forces Exerted on Receptor N -Glycans

Author: Scott, Mark, Marullo, Stefano, Doly, Stéphane, Saha, Kusumika, Enslen, Hervé, Scott, Mark George Hunter, Coureuil, Mathieu, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Neuro-Dol (Neuro-Dol), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Marullo, Stefano, [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), U1002, Pathogénie des infections systémiques (UMR_S 570), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and ANR-19-CE14-0045,MECAD-R,Activation mécanique, sucre-dépendante du récepteur ß2-adrénergique: un nouveau paradigme physiopathologique(2019)
Subjects: Mechanosensors, Context (language use), Stimulation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, shear stress, 03 medical and health sciences, Paracrine signalling, 0302 clinical medicine, Pharmacology (medical), Receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, G protein-coupled receptor, mechanotransduction, Pharmacology, 0303 health sciences, Chemistry, host- pathogen, lectins, Cell biology, pilins, sialic acid, Signal transduction, 030217 neurology & neurosurgery, Intracellular, Function (biology)
Abstract: International audience; Cells are sensitive to chemical stimulation which is converted into intracellular biochemical signals by the activation of specific receptors. Mechanical stimulations can also induce biochemical responses via the activation of various mechano-sensors. Although principally appreciated for their chemosensory function, G-protein-coupled receptors (GPCRs) may participate in mechano-transduction. They are indirectly activated by the paracrine release of chemical compounds secreted in response to mechanical stimuli, but they might additionally behave as mechano-sensors that are directly stimulated by mechanical forces. Although several studies are consistent with this latter hypothesis, the molecular mechanisms of a potential direct mechanical activation of GPCRs have remained elusive until recently. In particular, investigating the activation of the catecholamine β2-adrenergic receptor by a pathogen revealed that traction forces directly exerted on the N-terminus of the receptor via N-glycan chains activate specific signaling pathways. These findings open new perspectives in GPCR biology and pharmacology since most GPCRs express N-glycan chains in their N-terminus, which might similarly be involved in the interaction with cell-surface glycan-specific lectins in the context of cell-to-cell mechanical signaling.
Published: 2020

14. Eumitrins C-E: Structurally diverse xanthone dimers from the vietnamese lichen Usnea baileyi

Author: Pierre Le Pogam, Grégory Genta-Jouve, Solenn Ferron, Joël Boustie, Mehdi A. Beniddir, Van-Kieu Nguyen, Philippe Grellier, Warinthorn Chavasiri, Jean-François Gallard, Elisabeth Mouray, Thuc-Huy Duong, Chulalongkorn University [Bangkok], Laboratoire Ecologie, Evolution, Interactions des Systèmes amazoniens (LEEISA), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER)-Université de Guyane (UG)-Centre National de la Recherche Scientifique (CNRS), Hétérocycles et Peptides (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vietnam National University - Ho Chi Minh City (VNU-HCM), Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Equipe C-TAC (UMR 8638), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Graduate School, University of Texas, Austin, Chulalongkorn University, Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Seine-Université Paris-Seine-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)
Subjects: Circular dichroism, Magnetic Resonance Spectroscopy, Antiparasitic, medicine.drug_class, Stereochemistry, Xanthones, MESH: Molecular Structure, MESH: Plant Extracts, MESH: Usnea, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, MESH: Circular Dichroism, chemistry.chemical_compound, Drug Discovery, Xanthone, medicine, [CHIM]Chemical Sciences, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, Pharmacology, Molecular Structure, Plant Extracts, 010405 organic chemistry, Depsidone, MESH: Magnetic Resonance Spectroscopy, Circular Dichroism, MESH: Xanthones, Absolute configuration, General Medicine, Nuclear magnetic resonance spectroscopy, 0104 chemical sciences, Thallus, 010404 medicinal & biomolecular chemistry, Usnea, Vietnam, chemistry, MESH: Vietnam, Two-dimensional nuclear magnetic resonance spectroscopy
Abstract: International audience; Three new xanthone dimers, eumitrins C - E (1-3), along with a new depsidone, 3'-O-demethylcryptostictinolide (4) were isolated from the acetone extract of the whole thallus of the lichen Usnea baileyi collected in Vietnam. Their structures were unambiguously established by spectroscopic analyses (HRESIMS, 1D and 2D NMR), as well as comparison to literature data. The absolute configurations of 1-3 were elucidated through electronic circular dichroism (ECD) analyses. The absolute configuration of 2 was validated by comparison between experimental and TDDFT-calculated ECD spectra while that of 3 was based on DFT-NMR calculations and subsequent DP4 probability score. The antiparasitic activities against Plasmodium falciparum as well as the cytotoxic activity against seven cell lines were determined for the new compounds 1-3, and led from null to mild bioactivities.
Published: 2020

15. Genetic heterogeneity of polydactyly in Maine Coon cats

Author: Isabelle Vieira, Caroline Dufaure de Citres, Marie Abitbol, Laurent Tiret, Marion Fusellier, Bettina Duchenij, Emilie Filhol, Vincent Gache, Alexia Hamelin, Fabrice Conchou, Groupe de Recherches pour Animaux de Compagnie (GRAC), Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, PresUNAM, Université de Nantes (UN), Laboratoire des Maladies Rénales Héréditaires, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Animal Genetics Laboratory, Antagene, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Génétique fonctionnelle et médicale, Institut National de la Recherche Agronomique (INRA), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT), and École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)
Subjects: Male, Canada, [SDV]Life Sciences [q-bio], Population, Biology, 03 medical and health sciences, Genetic Heterogeneity, medicine, Animals, Small Animals, education, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Genetics, 0303 health sciences, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, CATS, Polydactyly, Genetic heterogeneity, 030305 genetics & heredity, medicine.disease, United States, Europe, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Cats, Female
Abstract: Objectives Polydactyly has been described in two breeds of domestic cats (Maine Coon and Pixie Bob) and in some outbred domestic cats (eg, Hemingway cats). In most cases, feline polydactyly is a non-syndromic preaxial polydactyly. Three variants located in a regulatory sequence involved in limb development, named ZRS (zone of polarising activity regulatory sequence), have been identified to be responsible for feline polydactyly. These variants have been found in outbred domestic cats in the UK ( UK1 and UK2 variants) and in Hemingway cats in the USA ( Hw variant). The aim of this study was to characterise the genetic features of polydactyly in Maine Coon cats. Methods Genotyping assay was used to identify the variant(s) segregating in a cohort of 75 polydactyl and non-polydactyl Maine Coon cats from different breeding lines from Europe, Canada and the USA. The authors performed a segregation analysis to identify the inheritance pattern of polydactyly in this cohort and analysed the population structure. Results The Hw allele was identified in a subset of polydactyl cats. Sequencing of two regulatory sequences involved in limb development did not reveal any other variant in polydactyl cats lacking the Hw allele. Additionally, genotype–phenotype and segregation analyses revealed the peculiar inheritance pattern of polydactyly in Maine Coon cats. The population structure analysis demonstrated a genetic distinction between Hw and Hw-free polydactyl cats. Conclusions and relevance Polydactyly in Maine Coon cats is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity, and this trait is characterised by genetic heterogeneity in the Maine Coon breed. Maine Coon breeders should be aware of this situation and adapt their breeding practices accordingly.
Published: 2020

16. PAK3 mutations responsible for severe intellectual disability and callosal agenesis inhibit cell migration

Author: Caroline Nava, Ferechté Razavi, Kevin Duarte, Jelena Martinovic, Jacqueline Cherfils, Jean-Vianney Barnier, Christel Depienne, Delphine Héron, Cyrille Mignot, Agnès Rastetter, Solveig Heide, Marie Laure Moutard, Tania Attié-Bitach, Véronique Rousseau, Sandrine Poëa-Guyon, Institut des Neurosciences Paris-Saclay (NeuroPSI), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institute of Human Genetics, University Hospital Essen, Embryology and genetics of human malformation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de foetopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Institut de Myologie, Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Sorbonne Université (SU), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Unité fonctionnelle de Fœtopathologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Laboratoire de biologie et pharmacologie appliquée (LBPA), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), Institut des Neurosciences de Paris-Saclay (Neuro-PSI), Department of genetics, Reference Center for Intellectual Disabilities of Rare Causes, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Department of Pediatrics Neurology, Reference Center for Intellectual Disabilities of Rare Causes, CHU Pitié-Salpêtrière [APHP], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Barnier, Jean-Vianney, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Microcephaly, Kinase, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Intellectual disability, Medizin, medicine.disease_cause, Severity of Illness Index, Protein Structure, Secondary, 0302 clinical medicine, Neurodevelopmental disorder, Cell Movement, Chlorocebus aethiops, Missense mutation, Child, Genetics, Mutation, [SDV.NEU.PC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Psychology and behavior, [SDV.NEU.SC]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Cognitive Sciences, Cell migration, Phenotype, Pedigree, [SDV] Life Sciences [q-bio], Neurology, COS Cells, αPIX/ARHGEF6, macromolecular substances, Biology, lcsh:RC321-571, 03 medical and health sciences, medicine, Animals, Humans, Amino Acid Sequence, Kinase activity, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Corpus Callosum Agenesis, Cell spreading, Cell adhesion, medicine.disease, Corpus callosum agenesis (CCA), HEK293 Cells, 030104 developmental biology, p21-Activated Kinases, PAK3, Agenesis of Corpus Callosum, 030217 neurology & neurosurgery
Abstract: International audience; Corpus callosum agenesis (CCA) is a brain malformation associated with a wide clinical spectrum including intellectual disability (ID) and an etiopathological complexity. We identified a novel missense G424R mutation in the X-linked p21-activated kinase 3 (PAK3) gene in a boy presenting with severe ID, microcephaly and CCA and his fetal sibling with CCA and severe hydrocephaly. PAK3 kinase is known to control synaptic plasticity and dendritic spine dynamics but its implication is less characterized in brain ontogenesis. In order to identify developmental functions of PAK3 impacted by mutations responsible for CCA, we compared the biochemical and biological effects of three PAK3 mutations localized in the catalytic domain. These mutations include two "se-vere" G424R and K389N variants (responsible for severe ID and CCA) and the "mild" A365E variant (responsible for nonsyndromic mild ID). Whereas they suppressed kinase activity, only the two severe variants displayed normal protein stability. Furthermore, they increased interactions between PAK3 and the guanine exchange factor αPIX/ARHGEF6, disturbed adhesion point dynamics and cell spreading, and severely impacted cell migration. Our findings highlight new molecular defects associated with mutations responsible for severe clinical phenotypes with developmental brain defects.
Published: 2020

17. Immunoglobulin Class Switch Recombination Defects

Author: Durandy, A., Kracker, S., Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV]Life Sciences [q-bio], [SDV.IMM]Life Sciences [q-bio]/Immunology, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030304 developmental biology, 030215 immunology
Abstract: International audience
Published: 2020

18. 16p13.11 microduplication in 45 new patients: refined clinical significance and genotype–phenotype correlations

Author: Aziza Lebbar, Sandra Chantot-Bastaraud, Catherine Yardin, Ghislaine Plessis, Patrick Edery, Damien Sanlaville, Laurence Faivre, Aline Receveur, Anne Claude Tabet, Solveig Heide, Laila El Khattabi, Patrick Callier, Christine Francannet, Alice Goldenberg, Eva Pipiras, Michèle Mathieu-Dramard, Chantal Missirian, Odile Boute-Benejean, Cécile Laroche, C. Francois-Fiquet, Pascal Garnier, Alice Masurel-Paulet, Nathalie Marle, Marion Gérard, Jean Michel Dupont, Alexandra Afenjar, Martine Doco Fenzy, Anne Moncla, Marie Pierre Cordier, Brigitte Benzacken, Jean-Hubert Caberg, Gaetan Lesca, Loïc de Pontual, Christine Ioos, Massimiliano Rossi, Nathalie Le Meur, Andrée Delahaye-Duriez, Joris Andrieux, Caroline Vincent-Delorme, Siham Chafai Elalaoui, Lesley Suiro, Philippe Vago, Anne-Laure Mosca-Boidron, Abdelhafid Natiq, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de génétique, CHU du Sart-Tilman, Laboratoire de Génétique Médicale, Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Trousseau [APHP], Unité Fonctionnelle de Génétique Clinique [CHU Pitié Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Génétique des Anomalies du Développement (GAD), Université de Bourgogne (UB)-IFR100 - Structure fédérative de recherche Santé-STIC, Unité de Génétique Médicale, Hôtel-Dieu-CHU Clermont-Ferrand, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de cytogénétique (CHU de Dijon), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU Amiens-Picardie, Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Jean Verdier [AP-HP], Handicaps génétiques de l'enfant (Inserm U393), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7), Raymond-Poincaré Hospital, Département de Génétique Médicale [INH Rabat], Institut National d'Hygiène, Rabat, Morocco, Service d'histologie, embryologie et cytogénétique [Béclère], Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Antoine Béclère [Clamart], Equipe de Recherche Médicale Appliquée (ERMA), Université de Limoges (UNILIM)-CHU Limoges-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), BIO-INGENIERIE (XLIM-BIO-INGENIERIE), XLIM (XLIM), Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS)-Université de Limoges (UNILIM)-Centre National de la Recherche Scientifique (CNRS), Service de Pédiatrie médicale [CHU Limoges], CHU Limoges, Génétique Médicale, CHU Clermont-Ferrand-CHU Estaing [Clermont-Ferrand], CHU Clermont-Ferrand, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Centre Hospitalier Universitaire de Liège (CHU-Liège), Hôpital Jeanne de Flandre [Lille], Centre Hospitalier Universitaire de Reims (CHU Reims), IFR53, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AP-HP Hôpital universitaire Robert-Debré [Paris], Hôpital Raymond Poincaré [AP-HP], Hôpital Maison Blanche, Hôpital Robert Debré, Hôpital Robert Debré-Centre Hospitalier Universitaire de Reims (CHU Reims), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Centre de recherche en neurosciences de Lyon (CRNL), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Université de Limoges (UNILIM)-CHU Limoges, and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, Pediatrics, Autism Spectrum Disorder, Developmental Disabilities, Disease, 030105 genetics & heredity, Neurodevelopmental disorder, Risk Factors, Gene Duplication, Medicine, Child, Genetics (clinical), miR-484, 3. Good health, Phenotype, Cardiovascular Diseases, Autism spectrum disorder, Child, Preschool, Speech delay, Female, medicine.symptom, Microtubule-Associated Proteins, NDE1, Adult, medicine.medical_specialty, Adolescent, Genetic counseling, MYH11, [SDV.CAN]Life Sciences [q-bio]/Cancer, Context (language use), Young Adult, 03 medical and health sciences, Intellectual Disability, mental disorders, Genetics, Humans, Abnormalities, Multiple, Clinical significance, Genetic Association Studies, business.industry, Infant, medicine.disease, neurodevelopmental disorder, 16p13.11 duplication, MicroRNAs, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, business, Neurocognitive, Chromosomes, Human, Pair 16
Abstract: BackgroundThe clinical significance of 16p13.11 duplications remains controversial while frequently detected in patients with developmental delay (DD), intellectual deficiency (ID) or autism spectrum disorder (ASD). Previously reported patients were not or poorly characterised. The absence of consensual recommendations leads to interpretation discrepancy and makes genetic counselling challenging. This study aims to decipher the genotype–phenotype correlations to improve genetic counselling and patients’ medical care.MethodsWe retrospectively analysed data from 16 013 patients referred to 12 genetic centers for DD, ID or ASD, and who had a chromosomal microarray analysis. The referring geneticists of patients for whom a 16p13.11 duplication was detected were asked to complete a questionnaire for detailed clinical and genetic data for the patients and their parents.ResultsClinical features are mainly speech delay and learning disabilities followed by ASD. A significant risk of cardiovascular disease was noted. About 90% of the patients inherited the duplication from a parent. At least one out of four parents carrying the duplication displayed a similar phenotype to the propositus. Genotype–phenotype correlations show no impact of the size of the duplicated segment on the severity of the phenotype. However, NDE1 and miR-484 seem to have an essential role in the neurocognitive phenotype.ConclusionOur study shows that 16p13.11 microduplications are likely pathogenic when detected in the context of DD/ID/ASD and supports an essential role of NDE1 and miR-484 in the neurocognitive phenotype. Moreover, it suggests the need for cardiac evaluation and follow-up and a large study to evaluate the aortic disease risk.
Published: 2018

19. A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

Author: Karin Pernet-Gallay, Amir Amiri-Yekta, Habib Latrous, Nicolas Landrein, Mélanie Bonhivers, Derrick R. Robinson, Zine-Eddine Kherraf, Raoudha Zouari, Nicolas Thierry-Mieg, Michael G. B. Blum, Pauline Le Tanno, Aminata Touré, Lazhar Halouani, Mounir Makni, Denis Dacheux, Christophe Arnoult, H Gourabi, Selima Fourati Ben Mustapha, Thomas Karaouzène, Serge Crouzy, Charles Coutton, Marie Christou-Kent, Mahmoud Kharouf, Guillaume Martinez, Ouafi Marrakchi, Pierre F. Ray, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), CHU de Grenoble, UM GI-DPI, 38000, Grenoble, France., Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACER, Tehran, 16635-148, Iran., Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Grenoble, UM de Génétique Chromosomique, Polyclinique les Jasmins [Tunis], Grenoble Neuroscience Institute, INSERM 1216, 38000, Grenoble, France., Laboratoire de Chimie et Biologie des Métaux (LCBM - UMR 5249), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Biologie Computationnelle et Mathématique (TIMC-IMAG-BCM), Techniques de l'Ingénierie Médicale et de la Complexité - Informatique, Mathématiques et Applications, Grenoble - UMR 5525 (TIMC-IMAG), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie Fondamentale et Pathogénicité (MFP), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR), Clinique de Promotion des Sciences de la Reproduction, Clinique de la reproduction les Jasmins, Equipe 1 : Physiopathologie du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-[GIN] Grenoble Institut des Neurosciences, Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-IMAG-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), and Génomique fonctionnelle des trypanosomatides (GFT)
Subjects: Male, 0301 basic medicine, Axoneme, Sequence analysis, [SDV]Life Sciences [q-bio], Flagellum, Biology, male infertility, Article, Cohort Studies, 03 medical and health sciences, Exon, 0302 clinical medicine, Testis, Exome Sequencing, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Genetics, Humans, Abnormalities, Multiple, Gene, ComputingMilieux_MISCELLANEOUS, Infertility, Male, Genetics (clinical), [SDV.GEN]Life Sciences [q-bio]/Genetics, Sperm flagellum, Calcium-Binding Proteins, Homozygote, Breakpoint, Dyneins, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Spermatozoa, Phenotype, spermatogenesis, sperm flagella, multiple morphological anomalies of the sperm flagella, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Flagella, Sperm Tail, Mutation, MMAF, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: International audience; Multiple morphological abnormalities of the sperm flagellum (MMAF) is a severe form of male infertility defined by the presence of a mosaic of anomalies, including short, bent, curled, thick, or absent flagella, resulting from a severe disorganization of the axoneme and of the peri-axonemal structures. Mutations in DNAH1, CFAP43, and CFAP44, three genes encoding axoneme-related proteins, have been described to account for approximately 30% of the MMAF cases reported so far. Here, we searched for pathological copy-number variants in whole-exome sequencing data from a cohort of 78 MMAF-affected subjects to identify additional genes associated with MMAF. In 7 of 78 affected individuals, we identified a homozygous deletion that removes the two penultimate exons of WDR66 (also named CFAP251), a gene coding for an axonemal protein preferentially localized in the testis and described to localize to the calmodulin- and spoke-associated complex at the base of radial spoke 3. Sequence analysis of the breakpoint region revealed in all deleted subjects the presence of a single chimeric SVA (SINE-VNTR-Alu) at the breakpoint site, suggesting that the initial deletion event was potentially mediated by an SVA insertion-recombination mechanism. Study of Trypanosoma WDR66's ortholog (TbWDR66) highlighted high sequence and structural analogy with the human protein and confirmed axonemal localization of the protein. Reproduction of the human deletion in TbWDR66 impaired flagellar movement, thus confirming WDR66 as a gene associated with the MMAF phenotype and highlighting the importance of the WDR66 C-terminal region.
Published: 2018

20. Clerodane furanoditerpenoids as the probable cause of toxic hepatitis induced by Tinospora crispa

Author: Sylvie Michel, Chouaha Bouzidi, Denis Boucaud-Maitre, Cyril Colas, Xavier Cachet, Ludivine Riffault-Valois, Jérôme Langrand, Annabelle Dugay, Equipe Pharmacognosie (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre antipoison de Paris, Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Direction de la recherche clinique et de l'innovation CHU Guadeloupe, Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Centre antipoison et de toxicovigilance (Paris) (CAPTV Paris), Université Paris Diderot - Paris 7 (UPD7)-Hôpitaux Universitaires Saint-Louis, Lariboisière, Fernand-Widal, Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Subjects: 0301 basic medicine, Toxic hepatitis, Male, Tinospora, Dioscorea bulbifera, Electrospray ionization, lcsh:Medicine, Context (language use), Article, Diterpenes, Clerodane, Teucrium, 03 medical and health sciences, 0302 clinical medicine, Liver Function Tests, Borapetoside C, medicine, Humans, lcsh:Science, ComputingMilieux_MISCELLANEOUS, Multidisciplinary, biology, Traditional medicine, Plant Stems, Chemistry, Plant Extracts, lcsh:R, Middle Aged, biology.organism_classification, 3. Good health, 030104 developmental biology, Phytochemical, Liver, 030220 oncology & carcinogenesis, [SHS.ENVIR]Humanities and Social Sciences/Environmental studies, lcsh:Q, medicine.symptom, Chemical and Drug Induced Liver Injury, Tinospora crispa
Abstract: Tinospora crispa is a popular traditional herbal plant commonly used throughout the world for treatment of various diseases, in particular type 2 diabetes mellitus. We report here a new case of toxic hepatitis in a 57-year old male patient in the French West Indies following the consumption of two aqueous extracts of fresh Tinospora crispa stems. It thus differs from two previously reported cases that concerned the chronic intake of powdered dry stems delivered in solid oral dosage forms (i.e. pellets and tablets). Liquid Chromatography-Diode Array Detection-Mass Spectrometry (LC/DAD/MS) analyses were performed on an aqueous extract of the offending sample that mimics the swallowed preparation. They revealed the presence of species-specific molecular marker borapetoside C (1) and thus enabled an unambiguous phytochemical identification. The exploration of tandem MS/MS data obtained by ultra-high performance liquid chromatography/electrospray ionization quadrupole time-of-flight mass spectrometry (UHPLC-ESI-QTOF-HRMS) allowed the identification of 17 additional cis-clerodane-type furanoditerpenoid lactones, analogues of 1. These results support the hypothesis that the mechanisms underlying hepatotoxicity of Tinospora crispa are the same as those encountered with furanoditerpenoids-containing plants such as Teucrium chamaedrys or Dioscorea bulbifera. In the context of type 2 diabetes treatment, we recommend that Tinospora crispa intake should be more closely monitored for signs of hepatotoxicity.
Published: 2018

21. The tetraspanin CD9 controls migration and proliferation of parietal epithelial cells and glomerular disease progression

Author: Lazareth, Hélène, Henique, Carole, Lenoir, Olivia, Puelles, Victor G., Flamant, Martin, Bollée, Guillaume, Fligny, Cécile, Camus, Marine, Guyonnet, Lea, Millien, Corinne, Gaillard, François, Chipont, Anna, Robin, Blaise, Fabrega, Sylvie, Dhaun, Neeraj, Camerer, Eric, Kretz, Oliver, Grahammer, Florian, Braun, Fabian, Huber, Tobias B., Nochy, Dominique, Mandet, Chantal, Bruneval, Patrick, Mesnard, Laurent, Thervet, Eric, Karras, Alexandre, Le Naour, François, Rubinstein, Eric, Boucheix, Claude, Alexandrou, Antigoni, Moeller, Marcus J., Bouzigues, Cédric, Tharaux, Pierre-Louis, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Génétique moléculaire de la neurotransmission et des processus neurodégénératifs (LGMNPN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Hôpital Saint-Antoine, Assistance Publique - Hôpitaux de Paris (AP-HP), Luxembourg Institute of Health (LIH), Systèmes Multi-Agents et Comportements (SMAC), Centre de Recherche en Informatique, Signal et Automatique de Lille (CRIStAL) - UMR 9189 (CRIStAL), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille, Département de recherche translationnelle, Institut Curie, Plateforme Vecteurs Viraux et Transfert de Gènes [SFR Necker] (VVTG), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Renal Division, Freiburg University Medical Center, Renal Division, University Medical Center Freiburg, Freiburg, Germany, Département de Pathologie [AP-HP Hôpital Européen Georges Pompidou], Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Des Maladies Rénales Rares aux Maladies Fréquentes, Remodelage et Réparation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de néphrologie adultes [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Physiopathologie et traitement des maladies du foie, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Paul Brousse, Microenvironnement et Physiopathologie de la Differenciation, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'optique et biosciences (LOB), École polytechnique (X)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paris-Centre de Recherche Cardiovasculaire [PARCC - UMR-S U970], Institut Cochin [IC UM3 (UMR 8104 / U1016)], Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires [LRI - EA4062], Génétique moléculaire de la neurotransmission et des processus neurodégénératifs [LGMNPN], Luxembourg Institute of Health [LIH], Systèmes Multi-Agents et Comportements [SMAC], Plateforme Vecteurs Viraux et Transfert de Gènes [SFR Necker] [VVTG], Centre de Recherche des Cordeliers [CRC (UMR_S 872)], Hôpital Européen Georges Pompidou [APHP] [HEGP], Laboratoire d'optique et biosciences [LOB], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Centre National de la Recherche Scientifique (CNRS)-Ecole Centrale de Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Ecole Centrale de Lille-Université de Lille, Institut Curie [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Université Paris-Sud - Paris 11 (UP11)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire d'Optique et Biosciences (LOB), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École polytechnique (X), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Department of Nephrology and Clinical Immunology [Aachen, Germany], Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University-RWTH Aachen University, Department of Medicine III [Hamburg, Germany] (Faculty of Medicine), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Department of Nephrology and Center for Inflammatory Diseases [Melbourne, VIC, Australia], Monash University [Melbourne], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Department of Renal Medicine [Scotland, UK], Royal Infirmary of Edinburgh, Renal Division [Freiburg, Germany], Service de néphrologie et de transplantation rénale [CHU Tenon], CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Néphrologie et Hémodialyse [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Paul Brousse-Université Paris-Sud - Paris 11 (UP11), Modèles de Cellules Souches Malignes et Thérapeutiques, This work was supported by Institut National de Santé et de la Recherche Médicale (INSERM), research grants from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ ERC grant agreement n°107037), European Research Projects on Rare Diseases E-Rare-2 JTC 2011 from l’Agence Nationale de la Recherche (ANR) of France and the Freiburg Institute for Advanced Studies to P.-L.T. We thank National Health and Medical Research Council of Australia, the Humboldt Foundation and German Society of Nephrology for supporting VGP. We are grateful to Assistance Publique des Hôpitaux de Paris for supporting H.L. We thank the European Research Council for supporting C.H. and O.L. We thank Nano-K for supporting the Laboratoire d’Optique et de Biosciences at Ecole Polytechnique., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Université de Lille-Ecole Centrale de Lille-Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Ecole Centrale de Lille-Centre National de la Recherche Scientifique (CNRS), Tharaux, Pierre-Louis, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH)-Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Service d'Urgences néphrologiques et transplantation rénale [CHU Tenon], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, [SDV]Life Sciences [q-bio], Science, Focal segmental glomerulosclerosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], urologic and male genital diseases, [SDV.MHEP.UN]Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, Article, Tetraspanin 29, Mice, Glomerulonephritis, Cell Movement, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.BC.BC] Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Animals, Humans, Cell migration, lcsh:Science, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS, Cell Proliferation, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Glomerulosclerosis, Focal Segmental, urogenital system, Epithelial Cells, [SDV.MHEP.UN] Life Sciences [q-bio]/Human health and pathology/Urology and Nephrology, female genital diseases and pregnancy complications, [SDV] Life Sciences [q-bio], Mice, Inbred C57BL, Mechanisms of disease, embryonic structures, Disease Progression, Female, Kidney Diseases, lcsh:Q, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and β1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions., In both focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN), kidney injury is characterised by the invasion of glomerular tufts by parietal epithelial cells (PECs). Here Lazareth et al. identify the tetraspanin CD9 as a key regulator of PEC migration, and find its upregulation in FSGS and CGN contributes to kidney injury in both diseases.
Published: 2019

22. Critical Role of a Sheath Phosphorylation Site On the Assembly and Function of an Atypical Type VI Secretion System

Author: Mathieu Coureuil, Ida Chiara Guerrera, Guénolé Prigent, Claire Lays, Monique Barel, Fabiola Tros, Nicholas H. Keep, Jason Ziveri, Alain Charbit, Anne Jamet, Cerina Chhuon, Héloïse Rytter, Thomas Henry, Pathogénie des infections systémiques (Inserm U1002), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme Protéomique Necker [SFR Necker] (PPN - 3P5), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Necker - Enfants Malades [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Pathogénie des infections systémiques (UMR_S 570), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Inflammasome, Bacterial Infections and Autoinflammation (I2BA), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of London [London], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Pathogénie des Staphylocoques – Staphylococcal Pathogenesis (StaPath), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre Régional de Pharmacovigilance (CRPV), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), U1002, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunité infection vaccination (I2V), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Charbit, Alain
Subjects: Proteomics, Stimulation, Biochemistry, Gas Chromatography-Mass Spectrometry, Analytical Chemistry, Cell Line, Potassium Chloride, 03 medical and health sciences, chemistry.chemical_compound, Bacterial Proteins, Tandem Mass Spectrometry, Humans, Secretion, Phosphorylation, Francisella tularensis, Molecular Biology, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Type VI secretion system, Alanine, 0303 health sciences, Electronic Data Processing, Phosphomimetics, biology, Molecular Structure, Research, Macrophages, 030302 biochemistry & molecular biology, Type VI Secretion Systems, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Cell biology, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, chemistry, Mutagenesis, Site-Directed, Francisella, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Protein Processing, Post-Translational, Biogenesis
Abstract: The bacterial pathogen Francisella tularensis possesses a noncanonical type VI secretion system (T6SS) that is required for phagosomal escape in infected macrophages. KCl stimulation has been previously used to trigger assembly and secretion of the T6SS in culture. By differential proteomics, we found here that the amounts of the T6SS proteins remained unchanged upon KCl stimulation, suggesting involvement of post-translational modifications in T6SS assembly. A phosphoproteomic analysis indeed identified a unique phosphorylation site on IglB, a key component of the T6SS sheath. Substitutions of Y139 with alanine or phosphomimetics prevented T6SS formation and abolished phagosomal escape whereas substitution with phenylalanine delayed but did not abolish phagosomal escape in J774-1 macrophages. Altogether our data demonstrated that the Y139 site of IglB plays a critical role in T6SS biogenesis, suggesting that sheath phosphorylation could participate to T6SS dynamics. Data are available via ProteomeXchange with identifier PXD013619; and on MS-Viewer, key lkaqkllxwx.
Published: 2019

23. Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease

Author: Josseline Kaplan, Tania Attié-Bitach, Christian P. Hamel, Christel Michel, Isabelle Perrault, Xavier Gérard, Sophie Thomas, Hélène Dollfus, Nicolas Goudin, Mickael Soussan, Iris Barny, Marlène Rio, Jean-Michel Rozet, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), CHU Necker - Enfants Malades [AP-HP], Embryology and genetics of human malformation (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Adult, Male, 0301 basic medicine, Adolescent, RNA Splicing, [SDV]Life Sciences [q-bio], Nonsense mutation, Mutant, Cell Cycle Proteins, Biology, Compound heterozygosity, medicine.disease_cause, Autoantigens, 03 medical and health sciences, Exon, 0302 clinical medicine, Retinal Diseases, Antigens, Neoplasm, Genetics, medicine, Humans, Cilia, Child, Eye Proteins, Molecular Biology, Genetics (clinical), Centrosome, Mutation, Tumor Suppressor Proteins, Cilium, Exons, General Medicine, Fibroblasts, Molecular biology, Exon skipping, Neoplasm Proteins, Cytoskeletal Proteins, Protein Transport, 030104 developmental biology, Codon, Nonsense, RNA splicing, Codon, Terminator, Female, 030217 neurology & neurosurgery
Abstract: International audience; CEP290 mutations cause a spectrum of ciliopathies from Leber congenital amaurosis type 10 (LCA10) to embryo-lethal Meckel syndrome (MKS). Using panel-based molecular diagnosis testing for inherited retinal diseases, we identified two individuals with some preserved vision despite biallelism for presumably truncating CEP290 mutations. The first one carried a homozygous 1 base-pair deletion in exon 17, introducing a premature termination codon (PTC) in exon 18 (c.1666del; p.Ile556Phefs*17). mRNA analysis revealed a basal exon skipping (BES) of exon 18, providing mutant cells with the ability to escape protein truncation, while disrupting the reading frame in controls. The second individual harbored compound heterozygous nonsense mutations in exon 8 (c.508A\textgreaterT, p.Lys170*) and exon 32 (c.4090G\textgreaterT, p.Glu1364*), respectively. Some CEP290 lacking exon 8 were detected in mutant fibroblasts but not in controls whereas some skipping of exon 32 occurred in both lines, but with higher amplitude in the mutant. Considering that the deletion of either exon maintains the reading frame in either line, skipping in mutant cells likely involves nonsense-associated altered splicing (NAS) alone (exon 8), or with BES (exon 32). Skipping of PTC-containing exons in mutant cells allowed production of CEP290 isoforms with preserved ability to assemble into a high molecular weight complex and to interact efficiently with proteins important for cilia formation and intraflagellar trafficking. In contrast, studying LCA10 and MKS fibroblasts we show moderate to severe cilia alterations, providing support for a correlation between disease severity and the ability of cells to express shortened, yet functional, CEP290 isoforms.
Published: 2018

24. Investigation of the hepatic development in the coculture of hiPSCs-derived LSECs and HLCs in a fluidic microenvironment

Author: Rachid Jellali, Morgane Le Gall, Françoise Gilard, Mathieu Danoy, Bertrand Gakière, Yukio Kato, Atsushi Miyajima, Eric Leclerc, Stéphane Poulain, Hiroshi Arakawa, Johanna Bruce, Marjorie Leduc, Yannick Tauran, Yuta Koui, Taketomo Kido, Yasuyuki Sakai, Charles Plessy, Laboratory for Integrated Micro Mechatronics Systems (LIMMS), The University of Tokyo (UTokyo)-Centre National de la Recherche Scientifique (CNRS), The University of Tokyo (UTokyo), Laboratoire des Multimatériaux et Interfaces (LMI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), RIKEN Center for Life Science Technologies (RIKEN CLST), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kanazawa University (KU), Institut des Sciences des Plantes de Paris-Saclay (IPS2 (UMR_9213 / UMR_1403)), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université d'Évry-Val-d'Essonne (UEVE)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and ANR-16-RHUS-0005,iLite,iLite(2016)
Subjects: Cell type, Angiogenesis, [SDV]Life Sciences [q-bio], Cell, Biomedical Engineering, Biophysics, Bioengineering, Biomaterials, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Medical technology, medicine, R855-855.5, Induced pluripotent stem cell, 030304 developmental biology, 0303 health sciences, Chemistry, Liver cell, GATA3, Articles, In vitro, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, TP248.13-248.65, Biotechnology
Abstract: International audience; Interactions between the different liver cell types are critical to the maintenance or induction of their function in vitro. In this work, human-induced Pluripotent Stem Cells (hiPSCs)-derived Liver Sinusoidal Endothelial Cells (LSECs) and Hepatocytes-Like Cells (HLCs) were cultured and matured in a microfluidic environment. Both cell populations were differentiated in Petri dishes, detached, and inoculated in microfluidic biochips. In cocultures of both cell types, the tissue has exhibited a higher production of albumin (3.19 vs 5.31 μg/mL/106 cells in monocultures and cocultures) as well as a higher inducibility CYP450 over monocultures of HLCs. Tubular-like structures composed of LSECs and positive for the endothelial marker PECAM1, as well as a tissue more largely expressing Stabilin-2 were detected in cocultures only. In contrast, monocultures exhibited no network and less specific endothelial markers. The transcriptomic analysis did not reveal a marked difference between the profiles of both culture conditions. Nevertheless, the analysis allowed us to highlight different upstream regulators in cocultures (SP1, EBF1, and GATA3) and monocultures (PML, MECP2, and NRF1). In cocultures, the multi-omics dataset after 14 days of maturation in biochips has shown the activation of signaling related to hepatic maturation, angiogenesis, and tissue repair. In this condition, inflammatory signaling was also found to be reduced when compared to monocultures as illustrated by the activation of NFKB and by the detection of several cytokines involved in tissue injury in the latter. Finally, the extracted biological processes were discussed regarding the future development of a new generation of human in vitro hepatic models.
Published: 2021

25. Liver Reptin/RUVBL2 controls glucose and lipid metabolism with opposite actions on mTORC1 and mTORC2 signalling

Author: Fadila Benhamed, Jean Rosenbaum, Joaquim Javary, Nicolas Saucisse, Pierre Costet, Marcio Do Cruzeiro, Corinne Buré, Capucine Heraud, Catherine Postic, Samira Benhamouche-Trouillet, Pierre Dubus, Rémi Pierre, Nestor Pallares-Lupon, Daniela Cota, Nathalie Allain-Courtois, Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, Université de Bordeaux (UB), Chimie et Biologie des Membranes et des Nanoobjets (CBMN), École Nationale d'Ingénieurs des Travaux Agricoles - Bordeaux (ENITAB)-Institut de Chimie du CNRS (INC)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), ANR-10-EQPX-0008,OPTOPATH,Innovations instrumentales et procédurales en psychopathologie expérimentale chez le rongeur(2010), ANR-15-CE14-0026,Hepatokind,FGF21 contrôle homéostasie glucidique via les facteurs de transcription ChREBP et PPARa(2015), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Mechanistic Target of Rapamycin Complex 2, mTORC1, Mechanistic Target of Rapamycin Complex 1, Biology, Diet, High-Fat, mTORC2, 03 medical and health sciences, Insulin resistance, Internal medicine, Glucose Intolerance, medicine, RUVBL2, Animals, ComputingMilieux_MISCELLANEOUS, PI3K/AKT/mTOR pathway, Adenosine Triphosphatases, Mice, Knockout, Lipogenesis, Body Weight, Fatty liver, DNA Helicases, Gastroenterology, [CHIM.MATE]Chemical Sciences/Material chemistry, Lipid Metabolism, medicine.disease, Fatty Liver, Disease Models, Animal, Glucose, 030104 developmental biology, Endocrinology, Liver, Hepatocytes, ATPases Associated with Diverse Cellular Activities, Insulin Resistance, Energy Metabolism, Homeostasis, Signal Transduction
Abstract: ObjectiveThe AAA+ ATPase Reptin is overexpressed in hepatocellular carcinoma and preclinical studies indicate that it could be a relevant therapeutic target. However, its physiological and pathophysiological roles in vivo remain unknown. This study aimed to determine the role of Reptin in mammalian adult liver.Design and resultsWe generated an inducible liver-specific Reptin knockout (RepinLKO) mouse model. Following Reptin invalidation, mice displayed decreased body and fat mass, hypoglycaemia and hypolipidaemia. This was associated with decreased hepatic mTOR protein abundance. Further experiments in primary hepatocytes demonstrated that Reptin maintains mTOR protein level through its ATPase activity. Unexpectedly, loss or inhibition of Reptin induced an opposite effect on mTORC1 and mTORC2 signalling, with: (1) strong inhibition of hepatic mTORC1 activity, likely responsible for the reduction of hepatocytes cell size, for decreased de novo lipogenesis and cholesterol transcriptional programmes and (2) enhancement of mTORC2 activity associated with inhibition of the gluconeogenesis transcriptional programme and hepatic glucose production. Consequently, the role of hepatic Reptin in the pathogenesis of insulin resistance (IR) and non-alcoholic fatty liver disease consecutive to a high-fat diet was investigated. We found that Reptin deletion completely rescued pathological phenotypes associated with IR, including glucose intolerance, hyperglycaemia, hyperlipidaemia and hepatic steatosis.ConclusionWe show here that the AAA +ATPase Reptin is a regulator of mTOR signalling in the liver and global glucido-lipidic homeostasis. Inhibition of hepatic Reptin expression or activity represents a new therapeutic perspective for metabolic syndrome.
Published: 2017

26. Antioxidant and Membrane Binding Properties of Serotonin Protect Lipids from Oxidation

Author: Catia Pereira, Karim El Kirat, Olivier Hermine, Caroline Le Van Kim, Sandrine Morandat, Hubert Santuz, Pascal Amireault, Francine Côté, Slim Azouzi, Yves Colin, Catherine Etchebest, Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA), Génie Enzymatique et Cellulaire (GEC), Université de Technologie de Compiègne (UTC)-Université de Picardie Jules Verne (UPJV)-Centre National de la Recherche Scientifique (CNRS), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biomécanique et Bioingénierie (BMBI), Université de Technologie de Compiègne (UTC)-Centre National de la Recherche Scientifique (CNRS), Dynamique des Structures et Interactions des Macromolécules Biologiques (DSIMB), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Transfusion Sanguine [Paris] (INTS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles (UA)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université de La Réunion (UR)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Transfusion Sanguine [Paris] (INTS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Serotonin, Erythrocytes, Antioxidant, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Membrane lipids, Lipid Bilayers, Biophysics, Molecular Dynamics Simulation, 01 natural sciences, Antioxidants, Lipid peroxidation, Membrane Lipids, 03 medical and health sciences, chemistry.chemical_compound, Lipid droplet, 0103 physical sciences, medicine, Humans, Receptor, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, Reactive oxygen species, Degree of unsaturation, Microscopy, Confocal, Membranes, 010304 chemical physics, Chemistry, Cell Membrane, Hydrogen Bonding, Flow Cytometry, 030104 developmental biology, Membrane, Biochemistry, Liposomes, lipids (amino acids, peptides, and proteins), Lipid Peroxidation, Hydrophobic and Hydrophilic Interactions, Oxidation-Reduction
Abstract: Serotonin (5-hydroxytryptamine, 5-HT) is a well-known neurotransmitter that is involved in a growing number of functions in peripheral tissues. Recent studies have shown nonpharmacological functions of 5-HT linked to its chemical properties. Indeed, it was reported that 5-HT may, on the one hand, bind lipid membranes and, on the other hand, protect red blood cells through a mechanism independent of its specific receptors. To better understand these underevaluated properties of 5-HT, we combined biochemical, biophysical, and molecular dynamics simulations approaches to characterize, at the molecular level, the antioxidant capacity of 5-HT and its interaction with lipid membranes. To do so, 5-HT was added to red blood cells and lipid membranes bearing different degrees of unsaturation. Our results demonstrate that 5-HT acts as a potent antioxidant and binds with a superior affinity to lipids with unsaturation on both alkyl chains. We show that 5-HT locates at the hydrophobic-hydrophilic interface, below the glycerol group. This interfacial location is stabilized by hydrogen bonds between the 5-HT hydroxyl group and lipid headgroups and allows 5-HT to intercept reactive oxygen species, preventing membrane oxidation. Experimental and molecular dynamics simulations using membrane enriched with oxidized lipids converge to further reveal that 5-HT contributes to the termination of lipid peroxidation by direct interaction with active groups of these lipids and could also contribute to limit the production of new radicals. Taken together, our results identify 5-HT as a potent inhibitor of lipid peroxidation and offer a different perspective on the role of this pleiotropic molecule.
Published: 2017

27. Chronic Granulomatous Disease in Patients Reaching Adulthood: A Nationwide Study in France

Author: Julie Bardet, Olivier Hermine, Fanny Lanternier, Nicolas Noel, Isabelle Durieu, Agathe Masseau, Olivier Lortholary, Felipe Suarez, Jacinta Bustamante, Bertrand Dunogue, Hélène Salvator, Benoit Pilmis, Marie-Anne Gougerot-Pocidalo, Stéphane Blanche, Fanny Fouyssac, Nizar Mahlaoui, Marc Lecuit, Harry Sokol, Emilie Catherinot, Vincent Barlogis, Caroline Elie, Alain Fischer, Louis-Jean Couderc, Hélène Coignard-Biehler, Karima Amazzough, Centre d'infectiologie Necker-Pasteur [CHU Necker], Institut Pasteur [Paris]-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département d'Immunologie, hématologie et rhumatologie pédiatriques [Hôpital Necker-Enfants malades - APHP], CHU Necker - Enfants Malades [AP-HP], Génétique Humaine des Maladies Infectieuses (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'informatique médicale et biostatistiques [CHU Necker], Université Paris Descartes - Paris 5 (UPD5), Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie et d'Oncologie Pédiatrique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service d'Onco-Hématologie Pédiatrique [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Service d'hématologie et immunologie, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Service de Pédiatrie et Hématologie Pédiatrique [CHU Timone, AP-HM], Hôpital de la Timone [CHU - APHM] (TIMONE), Service de médecine interne, Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de médecine interne et de pathologie vasculaire [hôpital Lyon sud, HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Microorganismes et Barrières de l'Hôte (Equipe avenir), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Adulte, Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Service d'immuno-hématologie pédiatrique [CHU Necker], The CEREDIH is supported by the French Association of Patients with Primary Immunodeficiencies and is funded by the French Ministry of Health. It additionally received unrestricted educational grants from Behring, Baxalta, Octapharma, and the patient associations AT-Europe and Trophée Guillaume., We thank all clinicians of the French national Centre de Référence des Déficits Immunitaires Héréditaires (CEREDIH) network for their help with this study. We also thank the CEREDIH staff: Chantal Andriamanga, Carolina Brito, Laurence Costes, Virginie Courteille, and Nathalie Devergnes., Institut Pasteur [Paris] (IP)-CHU Necker - Enfants Malades [AP-HP], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Collège de France - Chaire Médecine expérimentale (A. Fischer), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [Hôpital Foch, Suresnes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), St Giles laboratory of Human Genetics and Infectious Diseases, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris]-Université Paris Diderot - Paris 7 (UPD7), Equipe avenir Microorganismes et Barrières de l'Hôte, and Collège de France (CdF)
Subjects: Male, 0301 basic medicine, Pediatrics, MESH: Registries, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MESH: Granulomatous Disease, Chronic/diagnosis, Autoimmunity, Hematopoietic stem cell transplantation, chronic granulomatous disease, MESH: Granulomatous Disease, Chronic/complications, Granulomatous Disease, Chronic, 0302 clinical medicine, Chronic granulomatous disease, Cost of Illness, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, MESH: Bacterial Infections/etiology, MESH: Bacterial Infections/prevention & control, Registries, 030212 general & internal medicine, Child, [SDV.MP.MYC]Life Sciences [q-bio]/Microbiology and Parasitology/Mycology, High rate, MESH: France/epidemiology, MESH: Granulomatous Disease, Chronic/epidemiology, MESH: Bacterial Infections/epidemiology, MESH: Infant, Newborn, Age Factors, MESH: Mycoses/epidemiology, transition, Bacterial Infections, sequelae, MESH: Cost of Illness, MESH: Infant, Adult height, 3. Good health, Phenotype, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Infectious Diseases, Child, Preschool, Population Surveillance, MESH: Mycoses/drug therapy, MESH: Survival Analysis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, Symptom Assessment, Microbiology (medical), medicine.medical_specialty, adulthood, Adolescent, MESH: Mycoses/prevention & control, primary immunodeficiency, MESH: Phenotype, MESH: Population Surveillance, 03 medical and health sciences, MESH: Cross-Sectional Studies, MESH: Antibiotic Prophylaxis, MESH: Autoimmunity, MESH: Mycoses/etiology, medicine, Humans, In patient, MESH: Bacterial Infections/drug therapy, Retrospective Studies, MESH: Adolescent, MESH: Age Factors, MESH: Humans, business.industry, MESH: Symptom Assessment, MESH: Granulomatous Disease, Chronic/mortality, MESH: Child, Preschool, Infant, Newborn, Infant, MESH: Retrospective Studies, Retrospective cohort study, Antibiotic Prophylaxis, medicine.disease, Survival Analysis, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Male, Cross-Sectional Studies, 030104 developmental biology, Mycoses, Respiratory failure, Primary immunodeficiency, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Background : Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Method : Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Results : Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Conclusions : Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.
Published: 2017

28. Reversal of a Blunted Follicle-Stimulating Hormone by Chemotherapy in an Inhibin B–Secreting Adrenocortical Carcinoma

Author: Najiba Lahlou, Stéphanie Espiard, Estelle Louiset, Bertrand Dousset, Marie Bienvenu, Mathilde Sibony, Lionel Groussin, Jérôme Bertherat, Rossella Libé, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie hormonale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Saint-Vincent de Paul, Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Différenciation et communication neuronale et neuroendocrine (DC2N), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroendocrinologie cellulaire et moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de gynécologie et d'endocrinologie [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Saint-Vincent de Paul, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, endocrine system, Endocrinology, Diabetes and Metabolism, education, 030209 endocrinology & metabolism, Gonadotropin-releasing hormone, Case Reports, inhibin B, 03 medical and health sciences, Follicle-stimulating hormone, Cushing syndrome, 0302 clinical medicine, Internal medicine, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, adrenocortical carcinoma, Adrenocortical carcinoma, Mitotane, Adrenal, business.industry, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Endocrinology, 030220 oncology & carcinogenesis, tumor marker, business, Luteinizing hormone, Immunostaining, hormones, hormone substitutes, and hormone antagonists, Hormone, medicine.drug
Abstract: Context: Adrenocortical carcinomas (ACCs) are revealed in 60% of cases by steroid hypersecretion. Alternatively, it is uncommon to observe a paraneoplastic syndrome due to a peptide oversecretion. Case Description: We describe a 60-year-old man with a right adrenal mass. Hormonal evaluation showed an ACTH-independent Cushing syndrome. Surprisingly, follicle-stimulating hormone (FSH) levels were suppressed and blunted during gonadotropin-releasing hormone stimulation, despite normal luteinizing hormone levels. Levels of inhibin B, which negatively regulates the pituitary FSH, were very high. Given the atypical hormonal findings, an adrenal mass biopsy was performed, which allowed the diagnosis of an adrenocortical tumor (positive for steroidogenic factor-1 immunostaining). Moreover, an intense α-inhibin subunit immunostaining was observed. Because of the presence of metastases, the patient received mitotane and chemotherapy (etoposide and cisplatin). After 2 cycles, the inhibin B dropped. After 5 cycles, tumor size was reduced by 15%. Inhibin B levels remained low, and basal and gonadotropin-releasing hormone–stimulated FSH levels normalized. The patient underwent tumor resection, and pathology confirmed the ACC diagnosis (Weiss score of 9). The intensity of the α-inhibin subunit immunostaining was significantly decreased. Conclusions: We report the case of an inhibin B–secreting ACC in which the response to chemotherapy and mitotane was associated with a normalization of inhibin B secretion, allowing the reversal of the blunted FSH secretion. Inhibin B should be measured in case of suppressed FSH levels despite normal luteinizing hormone levels and may be considered a tumoral marker in some ACCs, even during treatment follow-up., Precis: We studied an adrenal mass with suppressed FSH levels, blunted after GnRH stimulation, and found an inhibin B–secreting adrenocortical carcinoma, in which inhibin B was normalized after chemotherapy.
Published: 2017

29. Elaboration of Sterically Hindered δ-Lactones through Ring-Closing Metathesis: Application to the Synthesis of the C1–C27 Fragment of Hemicalide

Author: François Sautel, Sabrina Dhambri, Guillaume Boissonnat, Camille Lecourt, Georges Massiot, Geoffroy Sorin, Srikanth Boinapally, Janine Cossy, Christophe Meyer, Janick Ardisson, Marie-Isabelle Lannou, Synthèse et Méthodes (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Chimie-Biologie-Innovation (UMR 8231) (CBI), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Pharmacochimie de la Régulation Epigénétique du Cancer (ETaC), PIERRE FABRE-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Chimie-Biologie-Innovation (CBI), Centre National de la Recherche Scientifique (CNRS)-Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris-Sciences-et-Lettres (https://www.psl.eu/)-Université Paris-Sciences-et-Lettres (https://www.psl.eu/)-Sorbonne Université (SU), and PIERRE FABRE-Centre National de la Recherche Scientifique (CNRS)
Subjects: Steric effects, [CHIM.ORGA]Chemical Sciences/Organic chemistry, 010405 organic chemistry, Organic Chemistry, chemistry.chemical_element, Hemicalide, 010402 general chemistry, 01 natural sciences, Combinatorial chemistry, 0104 chemical sciences, Catalysis, Ruthenium, Ring-closing metathesis, chemistry, Fragment (logic), Salt metathesis reaction
Abstract: International audience; The synthesis of the C1–C27 fragment of hemicalide, a marine metabolite displaying a unique potent antiproliferative activity, has been accomplished. The synthetic approach highlights a remarkably efficient ring-closing metathesis reaction catalyzed by Nolan ruthenium indenylidene complexes to elaborate the highly substituted δ-lactone framework.
Published: 2016

30. Strategies used by bacterial pathogens to cross the blood–brain barrier

Author: Xavier Nassif, Sandrine Bourdoulous, Mathieu Coureuil, Loic Le Guennec, Laboratoire d'Informatique, de Modélisation et d'optimisation des Systèmes (LIMOS), SIGMA Clermont (SIGMA Clermont)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Ecole Nationale Supérieure des Mines de St Etienne-Centre National de la Recherche Scientifique (CNRS)-Université Blaise Pascal - Clermont-Ferrand 2 (UBP), U1002, Pathogénie des infections systémiques (UMR_S 570), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-SIGMA Clermont (SIGMA Clermont)-Ecole Nationale Supérieure des Mines de St Etienne (ENSM ST-ETIENNE)-Centre National de la Recherche Scientifique (CNRS), and Université Blaise Pascal - Clermont-Ferrand 2 (UBP)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Sigma CLERMONT (Sigma CLERMONT)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure des Mines de St Etienne
Subjects: Virulence Factors, [SDV]Life Sciences [q-bio], Immunology, Biology, Neisseria meningitidis, medicine.disease_cause, Blood–brain barrier, Microbiology, 03 medical and health sciences, Virology, Streptococcus pneumoniae, medicine, Animals, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Inflammation, 0303 health sciences, Bacteria, 030306 microbiology, Streptococcus, Meninges, Brain, Endothelial Cells, Pathogenic bacteria, Biological Transport, medicine.disease, biology.organism_classification, 3. Good health, medicine.anatomical_structure, Blood-Brain Barrier, Meningitis
Abstract: The skull, spine, meninges, and cellular barriers at the blood-brain and the blood-cerebrospinal fluid interfaces well protect the brain and meningeal spaces against microbial invasion. However, once in the bloodstream, a range of pathogenic bacteria is able to reach the brain and cause meningitis. Despite advances in antibacterial therapy, bacterial meningitis remains one of the most important infectious diseases worldwide. The most common causative bacteria in children and adults are Streptococcus pneumoniae and Neisseria meningitidis associated with high morbidity and mortality, while among neonates, most cases of bacterial meningitis are due to group B Streptococcus and Escherichia coli. Here we summarise our current knowledge on the strategies used by these bacterial pathogens to survive in the bloodstream, to colonise the brain vasculature and to cross the blood-brain barrier.
Published: 2019

31. Mutations in TTC29, Encoding an Evolutionarily Conserved Axonemal Protein, Result in Asthenozoospermia and Male Infertility

Author: Marhaba Chaudhry, Sergey N. Savinov, Caroline Cazin, Gérard Gacon, Laurence Stouvenel, Abbas Daneshipour, Christophe Arnoult, Jean-Philippe Wolf, François Guillonneau, Raoudha Zouari, Pierre F. Ray, Maëlle Givelet, Jean-Fabrice Nsota Mbango, Alain Schmitt, Emmanuel Dulioust, Amir Amiri-Yekta, Lazhar Halouani, Denis Dacheux, Zeinab Sakheli, Patrick Lorès, Selima Fourati Ben Mustapha, Côme Ialy-Radio, Charles Coutton, Seyedeh Hanieh Hosseini, Aminata Touré, Lucile Ferreux, Maryline Favier, Mélanie Bonhivers, Zine-Eddine Kherraf, Catherine Patrat, Derrick R. Robinson, Ahmed Ziyyat, Ouafi Marrakchi, Elma El Khouri, Marjorie Whitfield, Marcio Do Cruzeiro, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Microbiologie cellulaire et moléculaire et pathogénicité (MCMP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), AGeing and IMagery (AGIM), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Service d'Histologie-Embryologie, Biologie de la Reproduction (CECOS Paris Cochin), CHU Cochin [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Clinique de Promotion des Sciences de la Reproduction - Les Jasmins (CPSR), Clinique de Promotion des Sciences de la Reproduction, Clinique de la reproduction les Jasmins, Polyclinique les Jasmins [Tunis], Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Génétique et Biologie du Développement, Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), University of Massachusetts [Amherst] (UMass Amherst), University of Massachusetts System (UMASS), Laboratoire des Venins et Toxines, Institut Pasteur de Tunis, Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratoire d'Histologie Embryologie - Biologie de la Reproduction, Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement (GReD ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Microbiologie Fondamentale et Pathogénicité (MFP), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-École Pratique des Hautes Études (EPHE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinique de Promotion des Sciences de la Reproduction [Tunis] (CPSR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-12-BSV1-0011,MUCOFERTIL,La protéine TAT1 (SLC26A8), partenaire et activateur de CFTR dans le spermatozoïde, au carrefour des infertilités masculines et de la mucoviscidose.(2012), and ANR-11-LABX-0024,ParaFrap,Alliance française contre les maladies parasitaires(2011)
Subjects: Male, 0301 basic medicine, Axoneme, Trypanosoma brucei brucei, TPR, Fertilization in Vitro, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Flagellum, Biology, Asthenozoospermia, sperm, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Article, Frameshift mutation, Evolution, Molecular, 03 medical and health sciences, 0302 clinical medicine, trypanosome, Trypanosomiasis, Intraflagellar transport, TTC29, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Genetics, medicine, Animals, Humans, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Gene, Infertility, Male, Genetics (clinical), mouse, asthenozoospermia, 030219 obstetrics & reproductive medicine, Sperm flagellum, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Sperm, Mice, Inbred C57BL, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Tetratricopeptide, 030104 developmental biology, Mutation, MMAF, Female, flagella, infertility, Microtubule-Associated Proteins
Abstract: International audience; In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on morphological abnormalities of the sperm flagellum (MMAF), a phenotype also termed "short tails," which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole-exome sequencing of a cohort of 167 MMAF-affected individuals, we identified bi-allelic loss-of-function mutations in more than 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a tetratricopeptide repeat-containing protein related to the intraflagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant, and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss-of-function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF.
Published: 2019

32. Magnetic resonance imaging presentation of deep infiltrating endometriosis nodules before and after pregnancy: A case series

Author: Bruno Borghese, Charles Chapron, Mathilde Bourdon, Louis Marcellin, François Goffinet, Pietro Santulli, Anne-Elodie Millischer, Chloé Maignien, Centre de Radiologie [Paris], Pôle femme-mère-enfant [Paris], Iimagerie médicale Paris centre Bachaumont [Paris] (IMPC Bachaumont)-Iimagerie médicale Paris centre Bachaumont [Paris] (IMPC Bachaumont), Service de Gynécologie Obstétrique II et Médecine de la Reproduction [Paris], Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Stress oxydant, prolifération cellulaire et inflammation, [Institut Cochin] Département Développement, Reproduction et Cancer (DRC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique, Epigénétique et Physiopathologie de la Reproduction, DHU Risques Et Grossesse, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Bodescot, Myriam
Subjects: Maternal Health, Biopsy, Endometriosis, Blood Pressure, Pathology and Laboratory Medicine, Vascular Medicine, 030218 nuclear medicine & medical imaging, Diagnostic Radiology, Labor and Delivery, 0302 clinical medicine, Pregnancy, Medicine and Health Sciences, 030219 obstetrics & reproductive medicine, Multidisciplinary, medicine.diagnostic_test, Radiology and Imaging, Obstetrics and Gynecology, Organ Size, Magnetic Resonance Imaging, 3. Good health, Obstetric Procedures, Hypertension, Medicine, Female, Radiology, Presentation (obstetrics), medicine.symptom, Anatomy, Research Article, Adult, medicine.medical_specialty, Imaging Techniques, Science, Bladder, Surgical and Invasive Medical Procedures, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Tertiary referral hospital, Research and Analysis Methods, Lesion, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, Hypertensive Disorders in Pregnancy, medicine, Humans, Retrospective Studies, business.industry, Biology and Life Sciences, Retrospective cohort study, Magnetic resonance imaging, Renal System, medicine.disease, Deep infiltrating endometriosis, Pregnancy Complications, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Lesions, Birth, Women's Health, business
Abstract: ObjectiveTo compare the magnetic resonance imaging (MRI) features of deep infiltrating endometriosis (DIE) lesions before and after pregnancy.DesignRetrospective study.SettingA single French university tertiary referral hospital.PatientsTwenty-one women without a prior history of surgery for endometriosis with a radiological diagnosis by MRI with two sets of examinations performed before and after pregnancy.InterventionsThe volumes of the lesions were compared using the same protocol before and after pregnancy based on MRI (1.5 T) examinations by a single experienced radiologist who is a referring practitioner for image-based diagnosis of endometriosis.Main outcome measure(s)The DIE lesion volume.Measurements and main resultsBetween October 2012 and December 2016, a total of 21 patients (67 lesions) were included and compared before and after pregnancy. The mean time interval between the MRI before pregnancy and delivery was 19.6 ± 8.5 months (median: 17.6, IQR 13.5-25.2 months). The mean time interval between delivery and the MRI after pregnancy was 11.0 ± 6.4 months (median: 8.3, IQR 6-15.2 months). The mean overall DIE lesion volume by MRI was significantly higher before pregnancy compared to after pregnancy (2,552 ± 3,315 mm3 vs. 1,708 ± 3,266 mm3, respectively, p < 0.01). The mean volume by MRI of the largest lesion of each patient was significantly higher before pregnancy compared to after pregnancy (4,728 ± 4,776 mm3 vs. 3165 ± 5299 mm3; p < 0.01).ConclusionOur data indicate a favorable impact of pregnancy on DIE lesion volumes as measured by MRI.
Published: 2019

33. Sialic acid mediated mechanical activation of β 2 adrenergic receptors by bacterial pili

Author: Virion, Zoé, Doly, Stéphane, Saha, Kusumika, Lambert, Mireille, Guillonneau, Francois, Bied, Camille, Duke, Rebecca, Rudd, Pauline, Robbe-Masselot, Catherine, Nassif, Xavier, Coureuil, Mathieu, Marullo, Stefano, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut du Fer à Moulin (IFM - Inserm U1270 - SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Ligue Nationale Contre le Cancer - Paris, Ligue Nationale Contre le Cancer (LNCC), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Glycobiologie Structurale et Fonctionnelle UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Département Endocrinologie, métabolisme, diabète (EMD) (EMD), Ligue Nationnale Contre le Cancer, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Recherche Agronomique (INRA)-Université de Lille-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; Meningococcus utilizes β-arrestin selective activation of endothelial cell β 2 adrenergic receptor (β 2 AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that β 2 AR activation requires two asparagine-branched glycan chains with terminally exposed N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues located at a specific distance in its N-terminus, while being independent of surrounding amino-acid residues. Meningococcus triggers receptor signaling by exerting direct and hemodynamic-promoted traction forces on β 2 AR glycans. Similar activation is recapitulated with beads coated with Neu5Ac-binding lectins, submitted to mechanical stimulation. This previously unknown glycan-dependent mode of allosteric mechanical activation of a G protein-coupled receptor contributes to meningococcal species selectivity, since Neu5Ac is only abundant in humans due to the loss of CMAH, the enzyme converting Neu5Ac into N-glycolyl-neuraminic acid in other mammals. It represents an additional mechanism of evolutionary adaptation of a pathogen to its host.
Published: 2019

34. TUBB1 mutations cause thyroid dysgenesis associated with abnormal platelet physiology

Author: Michel Polak, Catherine Strassel, Fabienne Jabot-Hanin, Claude Besmond, Frédéric Tores, Patrick Nitschke, Christine Bole-Feysot, Athanasia Stoupa, Carsten Janke, Anita Luise Michel, François Lanza, Dominique Lasne, Arnold Munnich, Frédéric Adam, Juliane Léger, Alexandre Kauskot, Alain Schmitt, Kathiresan Natarajan, Sanjay Gawade, Gabor Szinnai, Aurore Carré, Delphine Borgel, Dulanjalee Kariyawasam, Raphael Scharfmann, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), INSERM, UMR-S1176, Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion, Université de Strasbourg (UNISTRA)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Basel (Unibas), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Stress génotoxiques et cancer, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Paris-Sud - Paris 11 (UP11), Nutrition, inflammation et dysfonctionnement de l'axe intestin-cerveau (ADEN), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie et Diabétologie Pédiatriques, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Robert Debré, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Plate Forme Paris Descartes de Bioinformatique (BIP-D), Université Paris Descartes - Paris 5 (UPD5), Service de Génétique Médicale [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Pancréas endocrine et diabète de l'enfant, Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Pharmacie, Université Paris-Sud - Paris 11 (UP11), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Biologie et pharmacologie des plaquettes sanguines: hémostase, thrombose, transfusion (http://www.u949.inserm.fr/), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-EFS, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie, Université Paris-Sud - Paris 11 (UP11)-Institut Curie-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP]
Subjects: 0301 basic medicine, Medicine (General), Pathology, endocrine system diseases, Platelet Aggregation, [SDV]Life Sciences [q-bio], Physiology, Gene mutation, QH426-470, Mice, TUBB1, Tubulin, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Research Articles, Mice, Knockout, Hematology, TUBB1 Subject Categories Genetics, Thyroid, congenital hypothyroidism, Congenital hypothyroidism, 3. Good health, medicine.anatomical_structure, Thyroid Dysgenesis, Molecular Medicine, Research Article, Blood Platelets, endocrine system, medicine.medical_specialty, Protein family, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Gene Therapy & Genetic Disease, Thyroid dysgenesis, 03 medical and health sciences, R5-920, Internal medicine, Genetics, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], medicine, Animals, Humans, Gene, Abnormal Platelet, macroplatelets, business.industry, mutations, medicine.disease, 030104 developmental biology, Mutation, Genetics, Gene Therapy & Genetic Disease, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Haematology
Abstract: The genetic causes of congenital hypothyroidism due to thyroid dysgenesis (TD) remain largely unknown. We identified three novel TUBB1 gene mutations that co‐segregated with TD in three distinct families leading to 1.1% of TUBB1 mutations in TD study cohort. TUBB1 (Tubulin, Beta 1 Class VI) encodes for a member of the β‐tubulin protein family. TUBB1 gene is expressed in the developing and adult thyroid in humans and mice. All three TUBB1 mutations lead to non‐functional α/β‐tubulin dimers that cannot be incorporated into microtubules. In mice, Tubb1 knock‐out disrupted microtubule integrity by preventing β1‐tubulin incorporation and impaired thyroid migration and thyroid hormone secretion. In addition, TUBB1 mutations caused the formation of macroplatelets and hyperaggregation of human platelets after stimulation by low doses of agonists. Our data highlight unexpected roles for β1‐tubulin in thyroid development and in platelet physiology. Finally, these findings expand the spectrum of the rare paediatric diseases related to mutations in tubulin‐coding genes and provide new insights into the genetic background and mechanisms involved in congenital hypothyroidism and thyroid dysgenesis.
Published: 2019

35. Plasma Type I IFN Protein Concentrations in Human Tuberculosis

Author: Alba Llibre, Nicole Bilek, Vincent Bondet, Fatoumatta Darboe, Stanley Kimbung Mbandi, Adam Penn-Nicholson, Mark Hatherill, Flore Rozenberg, Thomas J. Scriba, Darragh Duffy, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Cape Town, Cellules dendritiques et lymphocytes B dans leur microenvironnement au cours des infections virales et du cancer, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the Strategic Health Innovation Partnerships (SHIP) Unit of the South African Medical Research Council with funds received from the South African Department of Science and Technology, the European Commission-funded TBVAC2020 consortium (H2020-PHC-643381), the Agence Nationale de la Recherche (ANR grant number CE17001002) and the Fondation Recherche Medical (FRM grant number SPF201170938617)., ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-16-CE17-0010,IFNX,Investigation des interferonopathies type I humaine(2016), European Project: 643381,H2020,H2020-PHC-2014-single-stage,TBVAC2020(2015), and Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, 0301 basic medicine, lcsh:QR1-502, Disease, IFNa, lcsh:Microbiology, IFNb, South Africa, Cellular and Infection Microbiology, Interferon, Child, Blood Proteins, interferon, Middle Aged, Brief Research Report, 3. Good health, Infectious Diseases, tuberculosis, Child, Preschool, Interferon Type I, Immune Mediators, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, France, medicine.symptom, medicine.drug, Adult, Microbiology (medical), Tuberculosis, 030106 microbiology, Immunology, Enzyme-Linked Immunosorbent Assay, Asymptomatic, Microbiology, Young Adult, 03 medical and health sciences, Immune system, medicine, Humans, Immunologic Factors, In patient, Gene, Aged, business.industry, Infant, Interferon-alpha, Interferon-beta, Mycobacterium tuberculosis, medicine.disease, 030104 developmental biology, protein biomarker, business
Abstract: International audience; Tuberculosis (TB) remains one of the leading causes of mortality worldwide, and a lack of understanding of basic disease pathogenesis is hampering development of new vaccines and treatments. Multiple studies have previously established a role for type I interferon (IFN) in TB disease. Type I IFNs are critical immune mediators for host responses to viral infection, yet their specific influence in bacterial infection remains unclear. As IFN-stimulated genes (ISGs) can have both stimulatory and inhibitory effects on immune function, clarifying the role of type I interferon in TB remains an important question. The quantification of interferon proteins in the circulation of patients has been restricted until the recent development of digital ELISA. To test the hypothesis that patients with active TB disease have elevated circulating type I IFN we quantified plasma IFNα and β proteins with Simoa digital ELISA in patients with active disease and asymptomatic M. tuberculosis infection. Strikingly no differences were observed between these two groups, while plasma from acute influenza infection revealed significantly higher plasma levels of both IFNα and IFNβ proteins. These results suggest a discordance between ISG mRNA expression by blood leukocytes and circulating type I IFN in TB.
Published: 2019

36. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Author: Dana Ranta, Jean Donadieu, Pekka Jaako, Alan J. Warren, Etienne Lengliné, Laetitia Kermasson, Christine Bellanné-Chantelot, Angela Hoslin, Alexandre Faille, Hubert Ducou Le Pointe, Patrick Revy, Abraham Acevedo-Arozena, Christine Bole-Feysot, Caroline Kannengiesser, Blandine Beaupain, Shengjiang Tan, Patrick Nitschke, Odile Fenneteau, Jean-Pierre de Villartay, Stefano Fumagalli, Maryline Poirée, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, CIC - Biotherapie - GHU Ouest APHP (CIC-BT 502), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Hematologie et Médecine Interne, Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Service de Pédiatrie, Unité d'Oncologie et Hématologie Pédiatrique, Centre Hospitalier Universitaire de Nice (CHU Nice), Service d'Hématologie Biologique [Hôpital Robert Debré, Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Radiologie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Plateforme de génomique [SFR Necker], Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Service d'hématologie-immunologie-oncologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), National History Museum of London, Acevedo-Arozena, Abraham [0000-0001-6127-7116], Bellanné-Chantelot, Christine [0000-0001-8415-6771], Warren, Alan J [0000-0001-9277-4553], Revy, Patrick [0000-0003-0758-8022], Apollo - University of Cambridge Repository, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service d'Hémato-oncologie Pédiatrique, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), CHU Saint-Antoine [APHP], Service d’oncologie hématologie pédiatrique [CHU Trousseau], Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Male, Models, Molecular, Ribosomopathy, Protein Conformation, DNA Mutational Analysis, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], medicine.disease_cause, Biochemistry, Ribosome, Mice, 0302 clinical medicine, Peptide Initiation Factors, Large ribosomal subunit, ComputingMilieux_MISCELLANEOUS, Cells, Cultured, Genetics, 0303 health sciences, Shwachman–Diamond syndrome, Mutation, Translation (biology), [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, Hematology, Shwachman-Diamond Syndrome, 3. Good health, Pedigree, Phenotype, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, EIF6, 030220 oncology & carcinogenesis, Female, Disease Susceptibility, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Immunology, Mice, Transgenic, Biology, 03 medical and health sciences, Structure-Activity Relationship, Red Cells, Iron, and Erythropoiesis, medicine, Animals, Humans, Ribonucleoprotein, U5 Small Nuclear, 030304 developmental biology, Whole Genome Sequencing, Infant, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, medicine.disease, Peptide Elongation Factors, Disease Models, Animal, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ribosome Subunits, Genome-Wide Association Study
Abstract: Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.
Published: 2019

37. Synthesis, 3D-structure and stability analyses of NRPa-308, a new promising anti-cancer agent

Author: Olivier Hermine, Rachid Benhida, Marie Fabre, Yves Lepelletier, Aurore Dumond, Wang-Qing Liu, Luc Demange, Christiane Garbay, Mohamed Selkti, Gilles Pagès, Cyril Ronco, Etienne Brachet, Françoise Raynaud, Philippe Belmont, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Centre Scientifique de Monaco, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Institut de Chimie de Nice (ICN), Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)
Subjects: Clinical Biochemistry, Anti-cancer agents, Pharmaceutical Science, Antineoplastic Agents, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Amide, Drug Discovery, medicine, [CHIM.CRIS]Chemical Sciences/Cristallography, Molecule, Humans, Neuropilins, Molecular Biology, NRPa-308 synthesis, Aqueous medium, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Cancer, medicine.disease, Combinatorial chemistry, Neuropilin-1, 0104 chemical sciences, 3. Good health, NRP-a308 stability, 010404 medicinal & biomolecular chemistry, Cancer cell, Molecular Medicine, Chemical stability, Human breast
Abstract: International audience; We report herein the synthesis of a newly described anti-cancer agent, NRPa-308. This compound antagonizes Neuropilin-1, a multi-partners transmembrane receptor overexpressed in numerous tumors, and thereby validated as promising target in oncology. The preparation of NRPa-308 proved challenging because of the ortho-gonality of the amide and sulphonamide bonds formation. Nevertheless, we succeeded a gram scale synthesis, according to an expeditious three steps route, without intermediate purification. This latter point is of utmost interest in reducing the ecologic impact and production costs in the perspective of further scale-up processes. The purity of NRPa-308 has been attested by means of conventional structural analyses and its crystallisation allowed a structural assessment by X-Ray diffraction. We also reported the remarkable chemical stability of this molecule in acidic, neutral and basic aqueous media. Eventually, we observed for the first time the accumulation of NRPa-308 in two types of human breast cancer cells MDA-MB231 and BT549. Tumor neoangiogenesis supplies cancer cells in oxygen and nutrients. Moreover, the neoformed blood vessels promote also the dissemination of malignant cells to healthy tissues. Therefore, tackling angiogenesis proved to be a relevant therapeutic option in oncology since more than 30 years.
Published: 2019

38. Pleiotropic effects of rfa-gene mutations on Escherichia coli envelope properties

Author: Jérôme F. L. Duval, Pascale Bauda, Marc Offroy, Audrey Beaussart, Céline Caillet, Stéphane Jomini, Marjorie Leduc, Christophe Pagnout, Héloïse Gendre, Angelina Razafitianamaharavo, Bénédicte Sohm, Laboratoire Interdisciplinaire des Environnements Continentaux (LIEC), Institut Ecologie et Environnement (INEE), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Terre et Environnement de Lorraine (OTELo), Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut national des sciences de l'Univers (INSU - CNRS)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Duval, Jerome
Subjects: Lipopolysaccharides, 0301 basic medicine, Cell biology, Cell Membrane Permeability, Proteome, [SDV]Life Sciences [q-bio], Mutant, Antimicrobial peptides, Population, lcsh:Medicine, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Gene mutation, Microscopy, Atomic Force, medicine.disease_cause, Article, [PHYS] Physics [physics], 03 medical and health sciences, 0302 clinical medicine, Escherichia coli, medicine, lcsh:Science, education, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, [PHYS]Physics [physics], education.field_of_study, Multidisciplinary, Chemistry, Escherichia coli Proteins, Cell Membrane, lcsh:R, Glycosyltransferases, Membrane Proteins, Bacteriology, Anti-Bacterial Agents, [SDV] Life Sciences [q-bio], 030104 developmental biology, Mutation, lcsh:Q, lipids (amino acids, peptides, and proteins), Cell envelope, Bacterial outer membrane, Biological physics, 030217 neurology & neurosurgery, Isobaric tag for relative and absolute quantitation
Abstract: International audience; Mutations in the rfa operon leading to severely truncated lipopolysaccharide (LPS) structures are associated with pleiotropic effects on bacterial cells, which in turn generates a complex phenotype termed deep-rough. Literature reports distinct behavior of these mutants in terms of susceptibility to bacteriophages and to several antibacterial substances. There is so far a critical lack of understanding of such peculiar structure-reactivity relationships mainly due to a paucity of thorough biophysical and biochemical characterizations of the surfaces of these mutants. In the current study, the biophysicochemical features of the envelopes of Escherichia coli deep-rough mutants are identified from the molecular to the single cell and population levels using a suite of complementary techniques, namely microelectrophoresis, Atomic Force Microscopy (AFM) and Isobaric Tag for Relative and Absolute Quantitation (iTRAQ) for quantitative proteomics. Electrokinetic, nanomechanical and proteomic analyses evidence enhanced mutant membrane destabilization/permeability, and differentiated abundances of outer membrane proteins involved in the susceptibility phenotypes of LPS-truncated mutants towards bacteriophages, antimicrobial peptides and hydrophobic antibiotics. In particular, inner-core LPS altered mutants exhibit the most pronounced heterogeneity in the spatial distribution of their Young modulus and stiffness, which is symptomatic of deep damages on cell envelope likely to mediate phage infection process and antibiotic action. Lipopolysaccharides (LPS) cover surface of the outer membrane of Gram-negative bacteria. They are tripar-tite molecules composed of lipid A, core oligosaccharides usually containing glucose, heptose, galactose, 2-keto-3-deoxyoctonate (KDO), and a highly variable O-antigen component (O-antigen is missing in Escherichia coli K-12). LPS act as a protective and permeable barrier against large molecules and hydrophobic compounds from the environment. They are positioned among phospholipids and proteins of the outer membrane, and contribute to the structural properties of the latter. In Escherichia coli, genes involved in the LPS synthesis are organized according to three operons in the rfa (also known as waa) locus (Fig. 1A). The first operon contains rfaD (or gmhD), rfaF, rfaC and rfaL genes. The three first genes encode proteins involved in the biosynthesis and transfer of the two first heptose residues in the inner core of LPS, whereas rfaL encodes a ligase required for the attachment of O-antigen. The second operon contains (i) rfaQ and rfaK (or waaU) that encodes the heptosyltransferases adding the third and fourth heptose residues, respectively, (ii) genes rfaG (or waaG), rfaI (or waaO) and rfaJ (or warR /waaJ) encoding the gluco-syltransferases that add the three glucose residues in the LPS outer core, (iii) rfaB that encodes the galactosyl-transferase adding the galactose residue to the first glucose, (iv) rfaY and rfaP that encodes kinases responsible for phosphorylation of heptoses, (v) rfaZ involved in the KDO attachment during LPS core biosynthesis, and finally (vi) rfaS that encodes a protein necessary for the attachment of rhamnose to the LPS core by linkage to the KDOII residue. The short kdtA operon contains kdtA (or waaA) that encodes the KDO transferase adding the two KDO residues to the lipid A and kdtB (or coaD) that is not involved in the LPS synthesis 1-3. A defining feature of E. coli LPS is the presence of phosphoryl substituents on the LPS core-heptose residues, essential for
Published: 2019

39. NHP2 deficiency impairs rRNA biogenesis and causes pulmonary fibrosis and Høyeraal-Hreidarsson syndrome

Author: Nicolas Pottier, Ibrahima Ba, Maname Benyelles, Emmanuelle Ollivier, Patrick Revy, Laetitia Kermasson, Elodie Lainey, Cécile Fourrage, Alicia Fernandes, Raphael Borie, Marie-Françoise O'Donohue, Caroline Kannengiesser, Chantal Lagresle-Peyrou, Hilario Nunes, Anne-Sophie Gamez, Bruno Crestani, Denis Caillaud, Fanny Morice-Picard, Jean-Pierre de Villartay, Isabelle Callebaut, Christelle Ménard, Clarisse Cazelles, Ambroise Marçais, Pierre-Emmanuel Gleizes, Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Hématologie Biologique, Hôpital Robert Debré, AP-HP, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center in Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de pneumologie [Avicenne], Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), The Clinical Bioinformatics laboratory (Equipe Inserm U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département pneumologie et addictologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de Pneumologie et Allergologie, CHU Clermont-Ferrand, Impact de l'environnement chimique sur la santé humaine - ULR 4483 (IMPECS), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Physiopathologie et Epidemiologie de l'Insuffisance Respiratoire, Laboratoire de biologie moléculaire eucaryote (LBME), Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Institut de minéralogie et de physique des milieux condensés (IMPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-IPG PARIS-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Hôpital Bichat - Claude Bernard, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Physique du Globe de Paris (IPG Paris)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE11-0029,RIBOMAN,Une approche intégrative de la biogenèse des ribosomes(2016), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Avicenne, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Impact de l'environnement chimique sur la santé humaine (IMPECS)
Subjects: 0301 basic medicine, Premature aging, Male, Telomerase, Transcription, Genetic, Pulmonary Fibrosis, Sequence Homology, Hoyeraal-Hreidarsson syndrome, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, medicine.disease_cause, Dyskerin, Dyskeratosis Congenita, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Intellectual Disability, Genetics, medicine, Humans, Amino Acid Sequence, Promoter Regions, Genetic, Molecular Biology, Genetics (clinical), Aged, Mutation, Fetal Growth Retardation, Infant, Newborn, Nuclear Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, Middle Aged, medicine.disease, Ribonucleoproteins, Small Nuclear, 3. Good health, Telomere, Pedigree, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, RNA, Ribosomal, 030220 oncology & carcinogenesis, Cancer research, Microcephaly, Female, Dyskeratosis congenita
Abstract: Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal–Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.
Published: 2019

40. VEGF (Vascular Endothelial Growth Factor) Functionalized Magnetic Beads in a Microfluidic Device to Improve the Angiogenic Balance in Preeclampsia

Author: Marylise Hebert-Schuster, Edouard Lecarpentier, Kelly Pons, Laurence Lecomte-Raclet, Stéphanie Descroix, Jean Guibourdenche, Lucile Alexandre, Laura Trapiella-Alfonso, Simon Dumas, Lucie Huart, Laurent Malaquin, Camille Fraichard, Isabelle Broutin, Thierry Fournier, Jean-François Gaucher, Michel Vidal, Nathalie Gagey-Eilstein, Vassilis Tsatsaris, Laboratoire de Physique et d'Etude des Matériaux (UMR 8213) (LPEM), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Physico-Chimie-Curie (PCC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Nanosciences et Innovation pour les Matériaux, la Biomédecine et l'Energie (ex SIS2M) (NIMBE UMR 3685), Institut Rayonnement Matière de Saclay (IRAMIS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et Pharmacotoxicologie Placentaire Humaine (U1139), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie et pharmacotoxicologie placentaire humaine : Microbiote pré & post natal (3PHM - UMR-S 1139), Équipe Ingénierie pour les sciences du vivant (LAAS-ELIA), Laboratoire d'analyse et d'architecture des systèmes (LAAS), Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université Toulouse Capitole (UT Capitole), Université de Toulouse (UT), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Laboratoire Physico-Chimie Curie [Institut Curie] (PCC), Institut Curie [Paris]-Institut de Chimie du CNRS (INC)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pierre-Gilles de Gennes pour la Microfluidique, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHI Créteil, Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), CIC - Mère Enfant Necker Cochin Paris Centre (CIC 1419), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hôpital Hôtel-Dieu [Paris], Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées (INSA)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées, Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse Capitole (UT Capitole), Descroix, Stephanie, Laboratoire de Physique et d'Etude des Matériaux (LPEM), Centre National de la Recherche Scientifique (CNRS)-ESPCI ParisTech-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie-Université Pierre et Marie Curie - Paris 6 (UPMC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut National Polytechnique (Toulouse) (Toulouse INP), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse 1 Capitole (UT1)-Université Toulouse - Jean Jaurès (UT2J), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse 1 Capitole (UT1), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse 1 Capitole (UT1), Equipe C-TAC (UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de biochimie-hormonologie, and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Robert Debré-Université Paris Diderot - Paris 7 (UPD7)
Subjects: Placental growth factor, Vascular Endothelial Growth Factor A, Endothelium, endothelium, placenta, [SDV]Life Sciences [q-bio], Endogeny, Pilot Projects, morbidity, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 030204 cardiovascular system & hematology, Pharmacology, In Vitro Techniques, Sensitivity and Specificity, Preeclampsia, preeclampsia, 03 medical and health sciences, chemistry.chemical_compound, Magnetics, 0302 clinical medicine, Pre-Eclampsia, Placenta, Lab-On-A-Chip Devices, Internal Medicine, medicine, Humans, Endothelial dysfunction, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Vascular Endothelial Growth Factor Receptor-1, Chemistry, medicine.disease, 3. Good health, Trophoblasts, Vascular endothelial growth factor, [SDV] Life Sciences [q-bio], Apheresis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, embryonic structures, Blood Component Removal, Angiogenesis Inducing Agents, Female, pregnancy, Blood Flow Velocity
Abstract: International audience; Preeclampsia is a hypertensive pregnancy disease associated with a massive increase in sFlt-1 (soluble form of the vascular endothelial growth factor 1) in the maternal circulation, responsible for angiogenic imbalance and endothelial dysfunction. Pilot studies suggest that extracorporeal apheresis may reduce circulating sFlt-1 and prolong pregnancy. Nonspecific apheresis systems have potential adverse effects because of the capture of many other molecules. Our concept is based on a specific and competitive apheresis approach using VEGF (vascular endothelial growth factor) functionalized magnetic beads to capture sFlt-1 while releasing endogenous PlGF (placental growth factor) to restore a physiological angiogenic balance. Magnetic beads were functionalized with VEGF to capture sFlt-1. Experiments were performed using PBS, conditioned media from human trophoblastic cells, and human plasma. The proof of concept was validated in dynamic conditions in a microfluidic device as an approach mimicking real apheresis. Magnetic beads were functionalized with VEGF and characterized to evaluate their surface ligand density and recognition capabilities. VEGF-coated magnetic beads proved to be an efficient support in capturing sFlt-1 and releasing PlGF. In static conditions, sFlt-1 concentration decreased by 33±13%, whereas PlGF concentration increased by 27±10%. In dynamic conditions, the performances were improved, with 40% reduction of sFlt-1 and up to 2-fold increase of free PlGF. The sFlt-1/PlGF ratio was reduced by 63% in the plasma of preeclamptic patients. Apheresis was also associated with VEGF release. A ligand-based approach using VEGF-coated beads is an effective approach to the capture of sFlt-1 and the release of endogenous PlGF. It offers new perspectives for the treatment of preeclampsia.
Published: 2019

41. ISCR-induced chlordecone dechlorination leads to derivatives with lower pro-angiogenic properties in vitro and in vivo on a prostate cancer model

Author: Legeay, Samuel, ALIBRAHIM, E. ALABED, Billat, P. A., Bristeau, Sébastien, Clere, N., Nesslany, F., Faure, S., Mouvet, Christophe, Micro et Nanomédecines Translationnelles (MINT), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bureau de Recherches Géologiques et Minières (BRGM) (BRGM), RENARD (TGE Réseau National de RPE interdisciplinaire - 3443), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-FR-CNRS 3443-Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), RENARD (TGE Réseau National de RPE interdisciplinaire - 3443 ), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Lille-Sorbonne Université (SU)-Aix Marseille Université (AMU)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Université de Strasbourg (UNISTRA)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Université de Lille-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])
Subjects: [SDU.STU.AG]Sciences of the Universe [physics]/Earth Sciences/Applied geology, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2019

42. 70 years of serotonin

Author: Cathy Vaillancourt, Francine Côté, Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Réseau International des Instituts Pasteur (RIIP)-Institut National de la Recherche Scientifique [Québec] (INRS)
Subjects: Serotonin, Stochastic Processes, 0303 health sciences, business.industry, Mental Disorders, MathematicsofComputing_GENERAL, General Medicine, Bioinformatics, Biochemistry, GeneralLiterature_MISCELLANEOUS, 03 medical and health sciences, InformationSystems_GENERAL, 0302 clinical medicine, Text mining, Osteogenesis, Receptors, Serotonin, Humans, Medicine, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, business, 030217 neurology & neurosurgery, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: International audience; Editorial
Published: 2019

43. FOXO1 transcription factor plays a key role in T cell—HIV-1 interaction

Author: Roux, Arthur, Leroy, Héloise, De Muylder, Bénédicte, Bracq, Lucie, Oussous, Samia, Dusanter-Fourt, Isabelle, Chougui, Ghina, Tacine, Rachida, Randriamampita, Clotilde, Desjardins, Delphine, Le Grand, Roger, Bouillaud, Frederic, Benichou, Serge, Margottin-Goguet, Florence, Cheynier, Remi, Bismuth, Georges, Mangeney, Marianne, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur de Shanghai, Académie des Sciences de Chine - Chinese Academy of Sciences (IPS-CAS), Réseau International des Instituts Pasteur (RIIP), Virus-Host Interactions for Therapeutic Targeting of Human Infection (VirHost), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, This work was supported by INSERM, CNRS, the 'proof of concept program' of Institut Cochin and the 'Agence Nationale de Rercherche sur le SIDA et les Hépatites virales' (ANRS, France)., Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Bodescot, Myriam
Subjects: RNA viruses, CD4-Positive T-Lymphocytes, Male, HIV Infections, Monkeys, Pathology and Laboratory Medicine, Lymphocyte Activation, Virus Replication, Biochemistry, White Blood Cells, Jurkat Cells, Immunodeficiency Viruses, Drug Metabolism, Animal Cells, Medicine and Health Sciences, Cell Cycle and Cell Division, Post-Translational Modification, Phosphorylation, ComputingMilieux_MISCELLANEOUS, Mammals, T Cells, Forkhead Box Protein O1, Cell Cycle, Eukaryota, Virus Latency, Medical Microbiology, Cell Processes, Viral Pathogens, Viruses, Vertebrates, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cellular Types, Pathogens, Macaque, Research Article, Primates, Cell Physiology, endocrine system, Immune Cells, Immunology, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Microbiology, Virology, Retroviruses, Old World monkeys, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, Pharmacokinetics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Microbial Pathogens, Pharmacology, Blood Cells, Lentivirus, Organisms, Biology and Life Sciences, HIV, Proteins, Cell Biology, Viral Replication, Cell Metabolism, Macaca fascicularis, Gene Expression Regulation, Amniotes, HIV-1, Virus Activation
Abstract: HIV-1 is dependent on the host cell for providing the metabolic resources for completion of its viral replication cycle. Thus, HIV-1 replicates efficiently only in activated CD4+ T cells. Barriers preventing HIV-1 replication in resting CD4+ T cells include a block that limits reverse transcription and also the lack of activity of several inducible transcription factors, such as NF-κB and NFAT. Because FOXO1 is a master regulator of T cell functions, we studied the effect of its inhibition on T cell/HIV-1 interactions. By using AS1842856, a FOXO1 pharmacologic inhibitor, we observe that FOXO1 inhibition induces a metabolic activation of T cells with a G0/G1 transition in the absence of any stimulatory signal. One parallel outcome of this change is the inhibition of the activity of the HIV restriction factor SAMHD1 and the activation of the NFAT pathway. FOXO1 inhibition by AS1842856 makes resting T cells permissive to HIV-1 infection. In addition, we found that FOXO1 inhibition by either AS1842856 treatment or upon FOXO1 knockdown induces the reactivation of HIV-1 latent proviruses in T cells. We conclude that FOXO1 has a central role in the HIV-1/T cell interaction and that inhibiting FOXO1 with drugs such as AS1842856 may be a new therapeutic shock-and-kill strategy to eliminate the HIV-1 reservoir in human T cells., Author summary HIV-1 is controlled by host restriction factors that interfere with its life cycle. However, the virus has equipped itself to counter these strategies. We report a new interplay between HIV-1 and human T lymphocytes through the FOXO1 transcription factor. By using AS1842856, a drug targeting FOXO1, we found that FOXO1 inhibition triggers metabolic activation and G0/G1 transition of resting T cells and also by the inactivation of the SAMHD1 viral restriction factor. FOXO1 inhibition makes resting CD4+ T cells permissive to HIV-1 infection. We finally found that pharmacologic (AS1842856 treatment) or genetic (shRNA) silencing of FOXO1 reactivate HIV-1 latent proviruses. Thus FOXO1 appears as an important player of the HIV-1/T-cell relationship and a new potential therapeutic target for intervention during HIV-1 infection.
Published: 2019

44. Insight into the mechanism of action of EP-39, a bevirimat derivative that inhibits HIV-1 maturation

Author: Aymeric Neyret, Bernard Gay, Anaïs Cransac, Laurence Briant, Pascale Coric, Serge Turcaud, Philippe Laugâa, Serge Bouaziz, Nathalie Chazal, Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Cibles Thérapeutiques et conception de médicaments (CiTCoM - UMR 8038), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques (LCBPT - UMR 8601), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Unité de Pharmacologie Chimique et Génétique (UPCG - UMR_S 640/UMR 8151), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Virologie et pathogenèse virale (VPV), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Laboratoire de cristallographie et RMN biologiques (LCRB - UMR 8015), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chazal, Nathalie, and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)
Subjects: 0301 basic medicine, Anti-HIV Agents, In silico, 030106 microbiology, Mutant, Assembly, Peptide, Virus Replication, Virus, Docking, Jurkat Cells, 03 medical and health sciences, chemistry.chemical_compound, Pr55Gag, Virology, Drug Resistance, Viral, Maturation, medicine, Humans, NMRStructure, ComputingMilieux_MISCELLANEOUS, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Pharmacology, chemistry.chemical_classification, Maturation inhibitors, Virus Assembly, Wild type, Structure, Succinates, NMR, Triterpenes, 3. Good health, Cell biology, Molecular Docking Simulation, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 030104 developmental biology, Mechanism of action, chemistry, Viral replication, Mutation, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, HIV-1, medicine.symptom, Bevirimat
Abstract: International audience; Maturation of human immunodeficiency virus type 1 (HIV-1) particles is a key step for viral infectivity. This process can be blocked using maturation inhibitors (MIs) that affect the cleavage of the capsid-spacer peptide 1 (CA-SP1) junction. Here, we investigated the mechanisms underlying the activity of EP-39, a bevirimat (BVM) derivative with better hydrosolubility. To this aim, we selected in vitro EP-39- and BVM-resistant mutants. We found that EP-39-resistant viruses have four mutations within the CA domain (CA-A194T, CA-T200N, CA-V230I, and CA-V230A) and one in the first residue of SP1 (SP1-A1V). We also identified six mutations that confer BVM resistance (CA-A194T, CA-L231F, CA-L231M, SP1-A1V, SP1-S5N and SP1-V7A). To characterize the EP-39 and BVM-resistant mutants, we studied EP-39 effects on mutant virus replication and performed a biochemical analysis with both MIs. We observed common and distinct characteristics, suggesting that, although EP-39 and BVM share the same chemical skeleton, they could interact in a different way with the Gag polyprotein precursor (Pr55Gag). Using an in silico approach, we observed that EP-39 and BVM present different predicted positions on the hexameric crystal structure of the CACTD-SP1 Gag fragment. To clearly understand the relationship between assembly and maturation, we investigated the impact of all identified mutations on virus assembly by expressing Pr55Gag mutants. Finally, using NMR, we have shown that the interaction of EP-39 with a peptide carrying the SP1-A1V mutation (CA-SP1(A1V)-NC) is almost suppressed in comparison with the wild type peptide. These results suggest that EP-39 and BVM could interact differently with the Pr55Gag lattice and that the mutation of the first SP1 residue induces a loss of interaction between Pr55Gag and EP-39.
Published: 2019

45. CSRP3 mediates polyphenols-induced cardioprotection in hypertension

Author: Jocelyne Hamelin, Helena L. A. Vieira, Valérie Nicolas, Patrizia Gena, Giuseppe Calamita, Morgane Le Gall, Cédric Broussard, Philippe Chaffey, Maria Mastrodonato, Cláudia N. Santos, Andreia Gomes, Antoinette Lemoine, Jean-Luc Perfettini, Catherine Brenner, Carole Oudot, Rodolphe Fischmeister, Centre de pharmacologie et innovation dans le diabète (CPID), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Centro de Estudos de Doenças Crónicas (CEDOC), NOVA Medical School - Faculdade de Ciências Médicas (NMS), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA)-Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Plateforme Recombinaison Homologue, Transfert d'Embryons et Cryoconservation [Institut Cochin] (PRHTEC), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dipartimento di Fisiologia Generale ed Ambientale, Università degli studi di Bari Aldo Moro (UNIBA), Radiothérapie moléculaire (UMR 1030), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), Physiopathogenèse et Traitement des Maladies du Foie [Villejuif], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Sud - Paris 11 (UP11), Signalisation et physiopathologie cardiaque, Université Paris-Sud - Paris 11 (UP11)-IFR141-Institut National de la Santé et de la Recherche Médicale (INSERM), Human Language Technology Interest Group (HULTIG), Universidade de Beira Interior, INSERM, UMR-S1180, Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre National de la Recherche Scientifique (CNRS), Universidade Nova de Lisboa (NOVA)-Universidade Nova de Lisboa (NOVA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Università degli studi di Bari, Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM), Universidade Nova de Lisboa = NOVA University Lisbon (NOVA), Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Plateforme protéomique 3P5 [Institut Cochin] (3P5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Radiothérapie Moléculaire et Innovation Thérapeutique (RaMo-IT), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Physiopathologie et traitement des maladies du foie, Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, and FISCHMEISTER, RODOLPHE
Subjects: Male, 0301 basic medicine, Cardiotonic Agents, Endocrinology, Diabetes and Metabolism, Metabolite, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Muscle Proteins, Cardiomegaly, Cardioprotection, 030204 cardiovascular system & hematology, Pharmacology, Biochemistry, Nitric oxide, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Fibrosis, medicine, Animals, Myocyte, Myocytes, Cardiac, CSRP3, Molecular Biology, Phenylephrine, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 2. Zero hunger, Rats, Inbred Dahl, Nutrition and Dietetics, Chemistry, Polyphenols, Sarcomere, Heart, Berries, LIM Domain Proteins, medicine.disease, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Disease Models, Animal, 030104 developmental biology, Strawberry tree, Fruit, Heart failure, Hypertension, medicine.drug
Abstract: International audience; Berries contain bioactive polyphenols, whose capacity to prevent cardiovascular diseases has been established recently in animal models as well in human clinical trials. However, cellular processes and molecular targets of berries polyphenols remain to be identified. The capacity of a polyphenol-enriched diet (i.e., blueberries, blackberries, raspberries, strawberry tree fruits and Portuguese crowberries berries mixture) to promote animal survival and protect cardiovascular function from salt-induced hypertension was evaluated in a chronic salt-sensitive Dahl rat model. The daily consumption of berries improved survival of Dahl/ salt-sensitive rats submitted to high-salt diet and normalized their body weight, renal function and blood pressure. In addition, a prophylactic effect was observed at the level of cardiac hypertrophy and dysfunction, tissue cohesion and cardiomyocyte hypertrophy. Berries also protected the aorta from fibrosis and modulated the expression of aquaporin-1, a channel involved in endothelial water and nitric oxide permeability. Left ventricle proteomics analysis led to the identification of berries and salt metabolites targets, including cystein and glycin-rich protein 3 (CSRP3), a protein involved in myocyte cytoarchitecture. In neonatal rat ventricular cardiomyocytes, CSRP3 was validated as a target of a berries-derived polyphenol metabolite, 4-methylcatechol sulfate, at micromolar concentrations, mimicking physiological conditions of human plasma circulation. Accordingly, siRNA silencing of CSRP3 and 4-methylcatechol sulfate pretreatment reversed cardiomyocyte hypertrophy and CSRP3 overexpression induced by phenylephrine. Our systemic study clearly supports the modulation of CSRP3 by a polyphenol-rich berries diet as an efficient cardioprotective strategy in hypertension-induced heart failure.
Published: 2019

46. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy

Author: Morgane Bomsel, Lin Xu, Z Zhou, S. Cristofari, Anne Hosmalin, Eliseo A. Eugenin, Fernando Real, Daniela Tudor, Sabrina Marion, Rémi Cheynier, Marc Revol, Alexis Sennepin, Ali Redha Zenak, Anne Couëdel-Courteille, Lisa Prevedel, Jean Pierre Jourdain, Yonatan Ganor, Charles-Antoine Dutertre, Alain Schmitt, Bénédicte Charmeteau, Claude Capron, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), [Institut Cochin] Departement Infection, immunité, inflammation, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Rutgers, The State University of New Jersey [New Brunswick] (RU), Rutgers University System (Rutgers), Université Paris Diderot - Paris 7 (UPD7), Pathogénie Virale, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie plastique et reconstructive [Hôpital Saint Louis], CHU Saint Louis [APHP], Institut Cochin (UMR_S567 / UMR 8104), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Plateforme imagerie de Microscopie Électronique [Institut Cochin], Service d'Hématologie et d'Immunologie [AP-HP Hôpital Ambroise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Bomsel, Morgane, and Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID
Subjects: CD4-Positive T-Lymphocytes, Male, Lipopolysaccharide, [SDV]Life Sciences [q-bio], Cell, HIV Infections, Virus Replication, Applied Microbiology and Biotechnology, chemistry.chemical_compound, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Receptor, ComputingMilieux_MISCELLANEOUS, Phytohaemagglutinin, 0303 health sciences, biology, virus diseases, Middle Aged, 3. Good health, medicine.anatomical_structure, Anti-Retroviral Agents, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA, Viral, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, Microbiology (medical), Sexual transmission, [SDV.IMM] Life Sciences [q-bio]/Immunology, Immunology, Microbiology, 03 medical and health sciences, Urethra, Genetics, medicine, Humans, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, Disease Reservoirs, 030304 developmental biology, 030306 microbiology, Activator (genetics), business.industry, Macrophages, RNA, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, chemistry, HIV-1, biology.protein, business, CD163
Abstract: Human immunodeficiency virus type 1 (HIV-1) eradication is prevented by the establishment on infection of cellular HIV-1 reservoirs that are not fully characterized, especially in genital mucosal tissues (the main HIV-1 entry portal on sexual transmission). Here, we show, using penile tissues from HIV-1-infected individuals under suppressive combination antiretroviral therapy, that urethral macrophages contain integrated HIV-1 DNA, RNA, proteins and intact virions in virus-containing compartment-like structures, whereas viral components remain undetectable in urethral T cells. Moreover, urethral cells specifically release replication-competent infectious HIV-1 following reactivation with the macrophage activator lipopolysaccharide, while the T-cell activator phytohaemagglutinin is ineffective. HIV-1 urethral reservoirs localize preferentially in a subset of polarized macrophages that highly expresses the interleukin-1 receptor, CD206 and interleukin-4 receptor, but not CD163. To our knowledge, these results are the first evidence that human urethral tissue macrophages constitute a principal HIV-1 reservoir. Such findings are determinant for therapeutic strategies aimed at HIV-1 eradication. Suppressive combination antiretroviral therapy fails to eradicate HIV-1 latent reservoirs in poorly characterized cell compartments. Here, urethral macrophages, but not urethral T cells, are shown to contain integrated HIV-1 DNA and to be able to release infectious HIV-1 following reactivation with lipopolysaccharide.
Published: 2019

47. Insights into Streptococcus agalactiae PI-2b pilus biosynthesis and role in adherence to host cells

Author: Cherry Gao, Patrick Trieu-Cuot, Claire Poyart, Bruno Périchon, Julie Guignot, Shaynoor Dramsi, Noémi Szili, Biologie des Bactéries pathogènes à Gram-positif - Biology of Gram-Positive Pathogens (BBPG+), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Barrières et Pathogènes, [Institut Cochin] Departement Infection, immunité, inflammation, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Cochin (IC UM3 (UMR 8104 / U1016)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre national de Référence des Streptocoques (CNR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by the DIM Malinf from the Conseil Régional d’Ile-de-France (Grant DIM130065) to CP and SD and the French Government's Investissement d’Avenir program, Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' Grant ANR-10-LABX-62-IBEID. NS was recipient of a doctoral fellowship from the DIM Malinf., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Group B Streptococcus, MESH: Streptococcus agalactiae / physiology, Operon, medicine.disease_cause, Bacterial Adhesion, Pilus, MESH: Adhesins, Bacterial / genetics, S. agalactiae, Cell Wall, Sortase, MESH: Phagocytosis, MESH: Endothelial Cells / microbiology, MESH: Humans Macrophages / microbiology, biology, Infectious Diseases, MESH: Adhesins, Bacterial / metabolism, MESH: Streptococcus agalactiae / pathogenicity, 030106 microbiology, Immunology, education, GBS, Microbiology, Streptococcus agalactiae, THP-1 phagocytosis, 03 medical and health sciences, Phagocytosis, Streptococcal Infections, medicine, PI-2b pilus, Humans, MESH: Streptococcal Infections / microbiology, MESH: Bacterial Adhesion, Adhesins, Bacterial, Gene, Macrophages, MESH: Fimbriae, Bacterial / metabolism, Endothelial Cells, MESH: Cell Wall / metabolism, biochemical phenomena, metabolism, and nutrition, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Streptococcus agalactiae / genetics, MESH: Operon / genetics, Bacterial adhesin, 030104 developmental biology, Fimbriae, Bacterial, Pilin, biology.protein, bacteria, Biogenesis
Abstract: International audience; The core PI-2b pilus present in "hypervirulent" ST-17 Streptococcus agalactiae strains consists of three pilin subunits (Spb1, Ap1 and Ap2) assembled by sortase SrtC1 and cell-wall anchored by Srt2. Spb1 was shown to be the major pilin and Ap2 the anchor pilin. Ap1 is a putative adhesin. Two additional genes, orf and lep, are part of this operon. The contribution of Lep and Ap1 to the biogenesis of the PI-2b pilus was investigated. Concerning the role of PI-2b, we found that higher PI-2b expression resulted in higher adherence to human brain endothelial cells and higher phagocytosis by human THP1 macrophages.
Published: 2019

48. Further terpenoids from Euphorbia tirucalli

Author: Dinh Hung Mac, Warinthorn Chavasiri, Pierre Le Pogam, Dinh-Phuoc Nguyen, Thi-Anh-Tuyet Nguyen, Mehdi A. Beniddir, Joël Boustie, Grégory Genta-Jouve, Kim-Phi-Phung Nguyen, Thuc-Huy Duong, Huu-Hung Nguyen, Ton Duc Thang University [Hô-Chi-Minh-City], Molécules bioactives, conception, isolement et synthèse (MBCIS), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), Equipe C-TAC (UMR 8638), Chimie Organique, Médicinale et Extractive et Toxicologie Expérimentale (COMETE - UMR 8638), Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Nguyen Tat Thanh University [Vietnam] (NTTU), Chulalongkorn University [Bangkok], Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Vietnam National University - Ho Chi Minh City (VNU-HCM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS), Nguyen Tat Thanh University, Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Supérieure de Chimie de Rennes-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)
Subjects: Sesquiterpene, Euphorbia tirucalli, Stereochemistry, Cell Survival, Euphane, Phytochemicals, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, 010402 general chemistry, 01 natural sciences, Tirucallane, chemistry.chemical_compound, Triterpene, Euphorbia tirucalli L, Euphorbia, Cell Line, Tumor, Drug Discovery, Humans, Pharmacology, chemistry.chemical_classification, biology, 010405 organic chemistry, Chemistry, Terpenes, Euphorbiaceae, General Medicine, [SDV.BV.BOT]Life Sciences [q-bio]/Vegetal Biology/Botanics, biology.organism_classification, Terpenoid, Triterpenes, 0104 chemical sciences, Phytochemical, Two-dimensional nuclear magnetic resonance spectroscopy, Heteronuclear single quantum coherence spectroscopy, Cadalene
Abstract: International audience; The phytochemical investigation of Euphorbia tirucalli L. (Euphorbiaceae) yielded four new compounds, including a rare cadalene-type sesquiterpene (tirucadalenone), two tirucallane triterpenoids, euphorol L and euphorol M, with the latter being described as an epimeric mixture, and a euphane triterpene, namely, euphorol N, together with 7 known compounds. Their structures and absolute configurations were elucidated from analysis of 1D (1H, J-modulated C) and 2D NMR (HSQC, HMBC and NOESY), high-resolution mass spectrometry (HRESIMS), optical rotation, and GIAO NMR shift calculation followed by CP3 analysis, along with comparison with literature reports. All these compounds were tested for cytotoxicity against K562, MCF-7 and/or and HepG2 tumor cell lines. Only tirucadalenone displayed a mild cytotoxic activity.
Published: 2019

49. Relevance of platelet desialylation and thrombocytopenia in type 2B von Willebrand disease: preclinical and clinical evidence

Author: Dupont, Annabelle, Soukaseum, Christelle, Cheptou, Mathilde, Adam, Frédéric, Nipoti, Thomas, Lourenco-Rodrigues, Marc-Damien, Legendre, Paulette, Proulle, Valérie, Rauch, Antoine, Kawecki, Charlotte, Bryckaert, Marijke, Rosa, Jean-Philippe, Paris, Camille, Ternisien, Catherine, Boisseau, Pierre, Goudemand, Jenny, Borgel, Delphine, Lasne, Dominique, Maurice, Pascal, Lenting, Peter J., Denis, Cécile V., Susen, Sophie, Kauskot, Alexandre, Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University College Cork (UCC), Hémostase et biologie vasculaire, Université Paris-Sud - Paris 11 (UP11)-IFR93-Institut National de la Santé et de la Recherche Médicale (INSERM), Hémostase et thrombose, Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Bordeaux (UB), Centre hospitalier universitaire de Nantes (CHU Nantes), Physiopathologie et pharmacologie cellulaires et moléculaires, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Lille 2 - Faculté de Médecine, Department of Hematology [Paris], Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratory of molecular mechanisms of hematologic disorders and therapeutic implications (ERL 8254 - Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurobiologie et Psychiatrie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Hématologie, PRES Université Lille Nord de France-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Blood Platelets, Male, Platelet Count, [SDV]Life Sciences [q-bio], Integrin beta3, von Willebrand Disease, Type 2, Prognosis, Thrombocytopenia, Article, N-Acetylneuraminic Acid, Platelet Biology & its Disorders, Mice, Polysaccharides, hemic and lymphatic diseases, Case-Control Studies, Mutation, von Willebrand Factor, Animals, Humans, Female, Integrin alpha2beta1, Protein Processing, Post-Translational, ComputingMilieux_MISCELLANEOUS, Follow-Up Studies
Abstract: Patients with type 2B von Willebrand disease (vWD) (caused by gain-of-function mutations in the gene coding for von Willebrand factor) display bleeding to a variable extent and, in some cases, thrombocytopenia. There are several underlying causes of thrombocytopenia in type 2B vWD. It was recently suggested that desialylation-mediated platelet clearance leads to thrombocytopenia in this disease. However, this hypothesis has not been tested in vivo. The relationship between platelet desialylation and the platelet count was probed in 36 patients with type 2B von Willebrand disease (p.R1306Q, p.R1341Q, and p.V1316M mutations) and in a mouse model carrying the severe p.V1316M mutation (the 2B mouse). We observed abnormally high elevated levels of platelet desialylation in both patients with the p.V1316M mutation and the 2B mice. In vitro, we demonstrated that 2B p.V1316M/von Willebrand factor induced more desialylation of normal platelets than wild-type von Willebrand factor did. Furthermore, we found that N-glycans were desialylated and we identified αIIb and β3 as desialylation targets. Treatment of 2B mice with sialidase inhibitors (which correct platelet desialylation) was not associated with the recovery of a normal platelet count. Lastly, we demonstrated that a critical platelet desialylation threshold (not achieved in either 2B patients or 2B mice) was required to induce thrombocytopenia in vivo. In conclusion, in type 2B vWD, platelet desialylation has a minor role and is not sufficient to mediate thrombocytopenia.
Published: 2019

50. Baboon envelope LVs efficiently transduced human adult, fetal, and progenitor T cells and corrected SCID-X1 T-cell deficiency

Author: David Fenard, Ornellie Bernadin, Anais Girard-Gagnepain, Camille Lévy, Chantal Lagresle-Peyrou, Kuiying Ma, Rana Mhaidly, Hanem Sadek, Marina Cavazzana, Fouzia Amirache, Caroline Costa, Ranjita Devi Moirangthem, Isabelle André, François-Loïc Cosset, Els Verhoeyen, Christian Reimann, Didier Nègre, Agata Cieslak, Vahid Asnafi, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Human Lymphohematopoiesis Laboratory (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lucerne Cantonal Hospital [Luzern, Switzerland], Généthon, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Clinical Investigation Center in Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (Equipe EVIR), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Genethon - Inserm UMR_S951, Immunologie moléculaire et biothérapies innovantes (IMBI), GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-GENETHON 3-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Évry-Val-d'Essonne (UEVE)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Généthon, Association française contre les myopathies (AFM-Téléthon)-Association française contre les myopathies (AFM-Téléthon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie moléculaire et biothérapies innovantes, École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Genethon-École pratique des hautes études (EPHE)-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Genethon-Généthon, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Human Virology Department, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Developpement Normal et Pathologique du Système Immunitaire, Université Nice Sophia Antipolis (UNS), Département de Biothérapie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP], Laboratoire d'Ingénierie des Systèmes Biologiques et des Procédés (LISBP), Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), and Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Recherche Agronomique (INRA)
Subjects: 0301 basic medicine, medicine.medical_treatment, Genetic enhancement, [SDV]Life Sciences [q-bio], CD34, chemical and pharmacologic phenomena, Mice, SCID, Hematopoietic stem cell transplantation, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, complex mixtures, Mice, 03 medical and health sciences, 0302 clinical medicine, Mice, Inbred NOD, medicine, Animals, Progenitor cell, ComputingMilieux_MISCELLANEOUS, Severe combined immunodeficiency, integumentary system, Stem Cells, Lentivirus, hemic and immune systems, Gene Therapy, Hematology, bacterial infections and mycoses, medicine.disease, T cell deficiency, 3. Good health, Cell biology, Haematopoiesis, 030104 developmental biology, 030220 oncology & carcinogenesis, Stem cell, Papio
Abstract: T cells represent a valuable tool for treating cancers and infectious and inherited diseases; however, they are mainly short-lived in vivo. T-cell therapies would strongly benefit from gene transfer into long-lived persisting naive T cells or T-cell progenitors. Here we demonstrate that baboon envelope glycoprotein pseudotyped lentiviral vectors (BaEV-LVs) far outperformed other LV pseudotypes for transduction of naive adult and fetal interleukin-7–stimulated T cells. Remarkably, BaEV-LVs efficiently transduced thymocytes and T-cell progenitors generated by culture of CD34+ cells on Delta-like ligand 4 (Dll4). Upon NOD/SCIDγC−/− engraftment, high transduction levels (80%-90%) were maintained in all T-cell subpopulations. Moreover, T-cell lineage reconstitution was accelerated in NOD/SCIDγC−/− recipients after T-cell progenitor injection compared with hematopoietic stem cell transplantation. Furthermore, γC-encoding BaEV-LVs very efficiently transduced Dll4-generated T-cell precursors from a patient with X-linked severe combined immunodeficiency (SCID-X1), which fully rescued T-cell development in vitro. These results indicate that BaEV-LVs are valuable tools for the genetic modification of naive T cells, which are important targets for gene therapy. Moreover, they allowed for the generation of gene-corrected T-cell progenitors that rescued SCID-X1 T-cell development in vitro. Ultimately, the coinjection of LV-corrected T-cell progenitors and hematopoietic stem cells might accelerate T-cell reconstitution in immunodeficient patients.
Published: 2019

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